US 20090291894A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0291894 A1 Tezapsidis et al. (43) Pub. Date: Nov. 26, 2009

(54) METHODS FORTREATING PROGRESSIVE Related U.S. Application Data COGNITIVE DSORDERS RELATED TO NEUROFIBRILLARY TANGLES (60) Provisional application No. 61/055,009, filed on May 21, 2008. (76) Inventors: Nikolaos Tezapsidis, West Orange, O O NJ (US); Steven Greco, Carlstadt, Publication Classification NJ (US) (51) Int. Cl. A638/22 (2006.01) CorrespondenceGREENBERG TRAURIG,Address: LLP (52)52) U.S. Cl.C ...... S14/12 200 PARKAVE., P.O. BOX 677 (57) ABSTRACT FLORHAMPARK, NJ 07932 (US) The described invention provides methods for treating or (21) Appl. No.: 12/470,427 preventing progression of a progressive cognitive disease, disorder or condition, and methods for improving resilience (22) Filed: May 21, 2009 of cognitive function in a subject in need thereof. Patent Application Publication Nov. 26, 2009 Sheet 1 of 4 US 2009/0291894 A1

Figure 1

Leptin (400 mg/ml) eptit (40th ingfml) - -- in 2 hr Air ess OB-R st kDa w x x w x Tau (pser") 5Sbs o-Tubulin 50 kDa - x ax 8 : x Total Tau

C D. Leptin (4) ng/ml) Leptin (4 tir) g Egtml 0 in h 2hr r 2S 40 6 8. So kDi- as we we won her Tata (pSer")386 5 50 kDa - 38 as Total Tag 28 & 40 E i -60 LeptinY (4 hr) -8 g gfin

20 S 8 .6

89 FCso : 750 mg/ml (46.9 nM) Patent Application Publication Nov. 26, 2009 Sheet 2 of 4 US 2009/0291894 A1

Figure 2

A. B. Insulin (10 M) insulin (10 M) i hr 2 hr 4 hr Ska are sex so e see Tau (pser') Sekiba- in two x. Tota Tal

insulin (10 M) insulin (4 hr)

mi ar 2. r 4 hr

Insulin (4 hr)

M

2 25 2.

-8 t ICso is 13.8 usf Patent Application Publication Nov. 26, 2009 Sheet 3 of 4 US 2009/0291894 A1

Figure 3

A. B. Lepio 4 hr eptin- 4 hr 100 ng/ml ------180g?m ------60 mgm ------600 ngs ------insulin - 4 hr suit is s a a 1 V3 ------20 ------2 M ------& wox Tala (pSer') g Siba Tota Tau 5 s s S. : &

C. D. Lepti- 4 hr Legis - 4 Br 3600 mg/ml - w - 600 mg/ml - h h slit. - 4 hr stain 4 hr 20 M ------20 M Sk: Tau (pSer')i so:00 58&da- 8&Tota: 8. a. r o: - CBS is Post Treatment & i.-2. -60; * - -8 - - 6 min hr - PBS Posi Treatment Patent Application Publication Nov. 26, 2009 Sheet 4 of 4 US 2009/0291894 A1

Figure 4

A B. AICAR (1 mM) AICAR (1 nM)

62)a AMPKa (pThr') Sis fixes Total AMPK, a

C. D. AICAR (1 mM)

5 Da.

Sks

E. AICAR (thr)

M M

0. 25 500 2

Cso as 2.7nM US 2009/029 1894 A1 Nov. 26, 2009

METHODS FOR TREATING PROGRESSIVE peptide' "amyloid f peptide' and AB include, but are not COGNITIVE DSORDERS RELATED TO limited to, AB40 (SEQID NO:4), AB42 (SEQID NO:5) and NEUROFIBRILLARY TANGLES AB43 (SEQID NO:6). The two major forms of AB are AB40 (SEQID NO:4), corresponding to a 40 amino acid-long pep CROSS REFERENCES tide and AB42 (SEQID NO:5), corresponding to a 42 amino acid-long peptide. Af43 (SEQID NO:6) corresponds to a 43 0001. This application claims the benefit of priority of amino acid-long AB peptide. U.S. application 61/055,009, filed May 21, 2008, incorpo 0009. It generally is believed that brain lipids are intri rated herein by reference in its entirety. cately involved in AB-related pathogenic pathways. The AB peptide is the major proteinaceous component of the amyloid STATEMENT OF GOVERNMENT FUNDING plaques found in the brains of AD patients and is regarded by 0002 This invention was made with government support many as the culprit of the disorder. The amount of extracel under Grant Number SBIR-1R43AG029670 awarded by lular AB accrued is critical for the pathobiology of AD and the National Institute on Aging. The government has certain depends on the antagonizing rates of its production/secretion rights in the invention. and its clearance. Studies have shown that neurons depend on the interaction between Presenilin 1 (“PS1) and Cytoplas FIELD OF THE INVENTION mic-Linker Protein 170 (“CLIP-170') to both generate AB and to take it up through the lipoprotein receptor related 0003. The described invention relates to methods for treat protein (“LRP) pathway. Further to this requirement, forma ing a progressive cognitive disorder and methods for improv tion of AB depends on the assembly of key proteins in lipid ing resilience of cognitive function. rafts (“LRs). The term “lipid rafts” as used herein refers to membrane microdomains enriched in cholesterol, glycosph BACKGROUND OF THE INVENTION ingolipids and glucosylphosphatidyl-inositol-(GPI)-tagged proteins implicated in signal transduction, protein trafficking Alzheimer's Disease and proteolysis. Within the LRs it is believed that AB's pre 0004 Alzheimer's disease (also called “AD”, “senile cursor, Amyloid Precursor Protein (APP), a type I mem dementia of the Alzheimer Type (SDAT) or “Alzheimer’s”) brane protein, is cleaved first by the protease B-secretase is a neurodegenerative disorder of the central nervous system (BACE) to generate the C-terminal intermediate fragment of (“CNS). AD is usually diagnosed clinically from the patient APP. CAPPB, which remains embedded in the membrane. history, collateral history from relatives, and clinical obser CAPPB subsequently is cleaved at a site residing within the Vations, based on the presence of characteristic neurological lipid bilayer by Y-secretase, a high molecular weight multi and neuropsychological features. protein complex containing presenilin, (PS1/PS2), nicastrin, 0005 AD is characterized by loss of neurons and synapses PEN-2, and APH-1 or fragments thereof. A? finally is in the cerebral cortex and certain Subcortical regions. This released outside the cell, where it may: i) start accumulating loss results in gross atrophy of the affected regions, including following oligomerization and exerting toxicity to neurons, degeneration in the temporal lobe and parietal lobe, and parts or ii) be removed either by mechanisms of endocytosis (in of the frontal cortex and cingulate gyrus. Both amyloid volving apolipoprotein-E (apoE) and LRP or Scavenger plaques (AP) and neurofibrillary tangles (“NFT) are Receptors) or by degradation by extracellular proteases clearly visible by microscopy in brains of those afflicted with including insulin-degrading enzyme (IDE) and neprilysin. AD. Plaques are dense, mostly insoluble deposits of amyloid 0010. It generally is believed that soluble AB oligomers, beta (AB) protein and cellular material outside and around prior to plaque buildup, exert neurotoxic effects leading to neurons. NFT are aggregates of the microtubule-associated neurodegeneration, synaptic loss and dementia. Further, protein “tau”, which have become hyperphosphorylated and increased A3 levels may result from abnormal lipid accumu accumulate inside the cells themselves. Although many older lation, thereby producing altered membrane fluidity and lipid individuals develop some plaques and tangles as a conse raft composition. quence of ageing, the brains of AD patients have a greater (0011. The presence of NFT is a characteristic of AD number of such plaques and tangles in specific brain regions, brains. These aggregations of hyperphosphorylated tau pro Such as the temporal lobe. tein also are referred to as “Paired Helical filaments” (PHF). 0006 AD is characterized histologically by the presence The role of PHF, whether as a primary causative factor in AD of extracellular amyloid deposits in the brain, together with or in a more peripheral role, is uncertain. However, the accu widespread neuronal loss. Extracellular amyloid deposits are mulation of PHF cause the destabilization of the microtubule known as neuritic or senile plaques. Amyloid deposits also network, thus compromising neuronal scaffolding and dis may be found within and around blood vessels. The main rupting cellular trafficking and signal transduction/commu protein constituent of AD and AD-like senile plaques is AB. nication, and leading to neuronal death. A? may be detected in plasma and cerebrospinal fluid (0012 NFT are not specific to AD; NFT also are seen in (“CSF) in vivo, and in cell culture media in vitro. Creutzfeldt-Jakob disease, Supranuclear Palsy, corticobasal 0007. The terms "amyloid peptide” “amyloid B peptide' neurodegeneration and Frontal temporal Dementia with Par and AB are used interchangeably herein to refer to the kinsonism linked to chromosome 17 (FTDP-17). This sug family of peptides generated through proteolytic processing gests that NFT may represent endpoints leading to neurode of the amyloid precursor protein (APP). generation, which may be generated by a number of causative 0008 APP exists as three different spliced isoforms, one events/insults. having 770 amino acids (isoform a) (SEQ ID NO:1), one having 751 amino acids (isoform b) (SEQID NO:2), and one Leptin having 695 amino acids (SEQID NO:3). The term “APP” as 0013 Leptin is a helical protein secreted by adipose tissue, used herein refers to all three isoforms. The terms "amyloid which acts on a receptor site in the Ventromedial nucleus of US 2009/029 1894 A1 Nov. 26, 2009 the hypothalamus to curb appetite and increase energy expen were prepared and analyzed by western blot with anti-tau diture as body fat stores increase. Leptin levels are 40% (pSer”). Membranes were stripped and re-probed with anti higher in women, and show a further 50% rise just before tau (total) for normalization. Representative blot is shown, menarche, later returning to baseline levels. Leptin levels are n=3. C. Normalized band densities from B were analyzed by lowered by fasting and increased by inflammation. densitometry. Results are presented as the meaniSD percent 0014 Human genes encoding both leptin and the leptin fold change, relative to placebo-treated Samples, which were receptor site have been identified. Laboratory mice having arbitrarily assigned a value of O. D. Induced cells were treated mutations on the ob gene, which encodes leptin, become with various concentrations of leptin for 4 hrs, or placebo. morbidly obese, diabetic, and infertile; administration of lep Experiments were then preformed as in B. E. Normalized tinto these mice improves glucose tolerance, increases physi band densitites from D were analyzed as in C. ICso represents cal activity, reduces body weight by 30%, and restores fertil the leptin concentration at which tau (pSer) phosphoryla ity. Mice with mutations of the db gene, which encodes the tion is decreased by 50 percent. p-0.05 vs. non-treated. leptin receptor, also become obese and diabetic but do not 0019 FIG.2 shows time- and dose-dependent dephospho improve with administration of leptin. Although mutations in rylation of tau by insulin in RA-SY5Y. A. RA-SY5Y were both the leptin and leptin receptor genes have been found in a treated with insulin (10 uM) for 4 hrs, or non-treated (pla small number of morbidly obese human subjects with abnor cebo). Whole cell extracts were prepared and analyzed by mal eating behavior, the majority of obese persons do not western blot with anti-insulin receptor (B-subunit). Mem show Such mutations, and have normal or elevated circulating branes were stripped and re-probed with anti-C-tubulin for levels of leptin. The immune deficiency seen in starvation normalization. Representative blot is shown, n=3. B. Whole may result from diminished leptin secretion. Mice lacking the cell extracts from cells treated for various times with insulin gene for leptin or its receptor show impairment of T-cell (10 uM), or placebo, were prepared and analyzed by western function, and, in laboratory studies, leptin has induced a blot with anti-tau (pSer'). Membranes were stripped and proliferative response in human CD4 lymphocytes. re-probed with anti-tau (total) for normalization. Represen 0015 Leptin also controls insulin sensitivity. Within the tative blot is shown, n=3. C. Normalized band densities from CNS, leptin crosses the blood brain barrier to bind specific B were analyzed by densitometry. Results are presented as the receptors in the brain to mediate food intake, body weight and meant-SD percent fold change, relative to placebo-treated energy expenditure. In general, (i) leptin circulates at levels samples, which were arbitrarily assigned a value of 0. D. proportional to body fat; (ii) leptin enters the CNS in propor Induced cells were treated with various concentrations of tion to its plasma concentration; (iii) leptin receptors are insulin for 4 hrs, or placebo. Experiments were then per found in brain neurons involved in regulating energy intake formed as in B. E. Normalized band densities from D were and expenditure; and (iv) leptin controls food intake and analyzed as in C. ICso represents the insulin concentration at energy expenditure by acting on receptors in the mediobasal which tau (pSer') phosphorylation is decreased by 50 per hypothalmus. cent. p-0.05 vs. non-treated. 0016. It generally is believed that leptin inhibits the activ 0020 FIG. 3 shows that combined treatment of leptin and ity of neurons that contain neuropeptideY (NPY) and agouti insulin produces a greater dephosphorylation of tau than related peptide (AgRP), and increases the activity of neurons either treatmentalone. A. RA-SY5Y were treated with low or expressing C.-melanocyte-stimulating hormone (C-MSH). high concentrations of leptin (100 or 1600 ng/ml) and/or The NPY neurons are a key element in the regulation of insulin (1 or 20LM) for 4 hrs, or non-treated (placebo). Whole appetite; small doses of NPY injected into the brains of cell extracts were prepared and analyzed by western blot with experimental animals stimulates feeding, while selective anti-tau (pSer'). Membranes were stripped and re-probed destruction of the NPY neurons in mice causes them to with anti-tau (total) for normalization. Representative blot is become anorexic. Conversely, C-MSH is an important media shown, n=3. B. Normalized band densities from A were ana tor of satiety, and differences in the gene for the receptor at lyzed by densitometry. Results are presented as the meaniSD which C-MSH acts in the brain are linked to obesity in percent fold change, relative to placebo-treated samples, humans. which were arbitrarily assigned a value of 0. C. Cells were 0017. It is not known how disturbances of production and treated for 4 hrs with leptin (1600 ng/ml) and insulin (20 uM), aggregation of AB peptide give rise to the pathology of AD or or placebo. To re-induce tau phosphorylation, cold PBS was other progressive cognitive disorders. There remains a need added to the post-treated cells for 10 min, 1 hr or not at all. for clinical therapy and diagnostic methods of progressive Experiments were then carried out as in A. D. Normalized cognitive disorders related to accumulation of neurofibrillary band densitites from C were analyzed as in B. p-0.05 vs. tangles. group. **p<0.01 vs. group BRIEF DESCRIPTION OF THE DRAWINGS (0021 FIG. 4 shows dephosphorylation of tau by 5'-AMP activated protein kinase (AMPK) activation in RA-SY5Y.A. 0018 FIG. 1 shows time- and dose-dependent dephospho Induced cells were treated with aminoimidazole carboxamide rylation of tau by leptin in RA-SY5Y. Human neuroblastoma ribonucleotide which acts as an AMP-activated protein kinase cells of the SY5Y cell line were induced for 7 days with agonist (AICAR) (1 mM) for 1 hr., or non-treated (placebo). retinoic acid (RA) (10 uM) to promote neuronal differentia Whole cell extracts were prepared and analyzed by western tion (RA-SY5Y). A. Induced cells were treated with leptin blot with AMPKC. (pThr' '). Membranes were stripped and (400 ng/ml) for 4 hrs, or non-treated (placebo). Whole cell re-probed with anti-C-AMPKC. (total) for normalization. extracts were prepared and analyzed by western blot with Representative blot is shown, n=3. B. Whole cell extracts anti-OB-R (leptin receptor). Membranes were stripped and from cells treated for various times with AICAR (1 mM), or re-probed with anti-C-tubulin for normalization. Representa placebo, were prepared and analyzed by western blot with tive blot is shown, n=3. B. Whole cell extracts from cells anti-tau (pSer'). Membranes were stripped and re-probed treated for various times with leptin (400 ng/ml), or placebo, with anti-tau (total) for normalization. Representative blot is US 2009/029 1894 A1 Nov. 26, 2009

shown, n=3. C. Normalized band densities from B were ana anti-fungal agent, an antiviral agent, an anti-protozoal agent, lyzed by densitometry. Results are presented as the meaniSD a steroidal anti-inflammatory agent, a non-steroidal anti-in percent fold change, relative to placebo-treated samples, flammatory agent, an anti-oxidant; a hormone; a vitamin; an which were arbitrarily assigned a value of 0. D. Induced cells antihistamine agent, and a chemotherapeutic agent. were treated with various concentrations of AICAR for 1 hr. or placebo. Experiments were then peformed as in B. E. DETAILED DESCRIPTION OF THE INVENTION Normalized band densitites from D were analyzed as in C. 0024. The described invention relates to methods for treat ICso represents the AICAR concentration at which tau ing or preventing a progressive cognitive disorder and meth (pSer) phosphorylation is decreased by 50 percent. *p-0. ods for improving resilience of cognitive function. 05 vs. non-treated. 0025. According to one aspect, the described invention provides a method for treating a progressive cognitive disor SUMMARY der, the method comprising the steps of: (a) administering to 0022. According to one aspect, the described invention a Subject in need thereof a first composition comprising (i) a provides a method for treating a progressive cognitive disor phosphorylated tau accumulation-modulating amount of a der, the method comprising the step of: (a) administering to a leptin composition, and (ii) a pharmaceutically acceptable Subject in need thereof a first composition comprising (i) a carrier, and (b) modulating accumulation of phosphorylated phosphorylated tau accumulation-modulating amount of a tau. in cerebrospinal fluid of the subject. leptin composition, or a pharmaceutically acceptable salt 0026. According to another aspect, the described inven thereof, and (ii) a pharmaceutically acceptable carrier, and (b) tion provides a method for preventing progression of a pro modulating accumulation of phosphorylated tau in cere gressive cognitive disorder, the method comprising the steps brospinal fluid of the subject. According to one embodiment of (a) administering to a subject in need thereof a first com of the method, the progressive cognitive disorder is selected position comprising (i) a phosphorylated tau accumulation from the group consisting of Alzheimer's Disease, progres modulating amount of a leptin composition, and (ii) a phar sive Supranuclear palsy, dementia, dementia pugilistica, maceutically acceptable carrier, and (b) modulating Creutzfeldt-Jakob disease, frontotemporal dementia, Pick's accumulation of phosphorylated tau in cerebrospinal fluid of disease, and FTDP-17 (parkinsonism) corticobasal degenera the subject. tion. According to another embodiment, the leptin composi 0027. According to one embodiment, the leptin composi tion is a leptin, or a pharmaceutically acceptable salt thereof. tion comprises a leptin, or a pharmaceutically acceptable salt According to another embodiment, the leptin composition is thereof. According to another embodiment, the leptin com a leptin mimic, or a pharmaceutically acceptable salt thereof. position comprises a leptin mimic, or a pharmaceutically According to another embodiment, the leptin composition is acceptable salt thereof. According to another embodiment, a leptin derivative, or a pharmaceutically acceptable salt the leptin composition comprises a leptin derivative, or a thereof. According to another embodiment, the leptin com pharmaceutically acceptable salt thereof. According to position is a leptin agonist, or a pharmaceutically acceptable another embodiment, the leptin composition comprises a lep salt thereof. According to another embodiment, the phospho tin agonist, or a pharmaceutically acceptable salt thereof. rylated tau accumulation-modulating amount is an amount According to another embodiment, the leptin composition from about 0.01 mg/kg body weight to about 100 mg/kg body comprises an AMP-dependent protein kinase activator, or a weight. According to another embodiment, the first compo pharmaceutically acceptable salt thereof. According to sition further comprises a second therapeutic agent. Accord another embodiment, the leptin composition comprises a ing to another embodiment, the second therapeutic agent is at mimic of a leptin blocker, or a pharmaceutically acceptable least one of an antibiotic, an anti-fungal agent, an antiviral salt thereof. According to another embodiment, the leptin agent, an anti-protozoal agent, a steroidal anti-inflammatory composition comprises a leptin antagonist, or a pharmaceu agent, a non-steroidal anti-inflammatory agent, an anti-oxi tically acceptable salt thereof. According to another embodi dant; a hormone; a vitamin; an antihistamine agent, and a ment, the leptin composition comprises an AMP-dependent chemotherapeutic agent. According to another embodiment, protein kinase inhibitor, or a pharmaceutically acceptable salt the progressive disorder comprises accumulation of neu thereof. rofibrillary tangles in brain. 0028. According to another embodiment, the leptin com 0023. According to another aspect, the described inven position comprises at least one of a leptin, a leptin mimic, a tion provides a method for improving resilience of cognitive leptin derivative, a leptin agonist, an AMP-dependent protein function in a subject in need thereof, the method comprising kinase activator, a mimic of a leptin blocker, a leptin antago the steps of (a) administering to the Subject a composition nist, an AMP-dependent protein kinase inhibitor, or pharma comprising (i) a cognitive function-enhancing amount of a ceutically acceptable salts thereof. leptin composition, and (ii) a pharmaceutically acceptable (0029. The term “treat” or “treating as used herein refers carrier; and (b) modulating accumulation of phosphorylated to accomplishing one or more of the following: (a) reducing tau in cerebrospinal fluid of the Subject. According to one the severity of the disorder; (b) limiting development of embodiment of the method, the leptin composition comprises symptoms characteristic of the disorder(s) being treated; (c) at least one of a leptin, a leptin mimic, a leptin derivative, an limiting worsening of symptoms characteristic of the disorder AMP-dependent protein kinase activator, a leptin agonist, a (s) being treated; (d) limiting recurrence of the disorder(s) in leptin blocker, a mimic of a leptin blocker, a leptin antagonist, patients that have previously had the disorder(s); and (e) an AMP-dependent protein kinase inhibitor; or pharmaceuti limiting recurrence of symptoms in patients that were previ cally acceptable salts thereof. According to another embodi ously symptomatic for the disorder(s). ment, the leptin composition further comprises a second 0030. The term “reduce” or “reducing as used herein therapeutic agent. According to another embodiment, the sec refers to limit occurrence of the disorder in individuals at risk ond therapeutic agent is at least one of an antibiotic, an of developing the disorder. US 2009/029 1894 A1 Nov. 26, 2009

0031. The term “modulate” as used herein means to regu 0038 A subject in need thereof is a patient having, or at late, alter, adapt, or adjust to a certain measure or proportion. risk of having, a progressive cognitive disease. 0032. The term “disease' or “disorder as used herein 0039. The term “dementia as used herein refers to a refers to an impairment of health or a condition of abnormal decline or a progressive decline in cognitive function due to functioning. The term "syndrome, as used herein, refers to a damage or disease in the brain beyond what might be pattern of symptoms indicative of some disease or condition. expected from normal aging. The term “cognitive function” The term "injury, as used herein, refers to damage or harm to refers to the intellectual processes resulting in an understand a structure or function of the body caused by an outside agent ing, perception, or awareness of one's ideas as well as the or force, which may be physical or chemical. The term “con ability to perform mental tasks, such as thinking, learning, dition', as used herein, refers to a variety of health states and judging, remembering, computing, controlling motor func is meant to include disorders or diseases caused by any under tions, and the like. lying mechanism or disorder, injury, and the promotion of 0040. The term "peptidomimetic' refers to a small pro healthy tissues and organs. tein-like chain designed to mimic or imitate a peptide. A 0033 Progressive cognitive disorders include, but are not peptidomimetic may comprise non-peptidic structural ele limited to, progressive Supranuclearpalsy, dementia; demen ments capable of mimicking (meaning imitating) or antago tia pugilistica; AD; Creutzfeldt-Jakob disease; frontotempo nizing (meaning neutralizing or counteracting) the biological ral dementia; Pick's disease; other tau-positive pathology action(s) of a natural parent peptide. The terms "leptin pep including FTDP-17 (parkinsonism) corticobasal degenera tidomimetic” “leptin mimic’, and “leptin mimetic' are used tion; frontotemporal lobar degeneration (FTLD): dementia interchangeably hereinto refer to a leptin derivative compris lacking distinctive histology. ing a functional domain of a leptin protein that produces a 0034. The term “administering as used herein refers to biological effect. In chemistry, a derivative is a compound that causing to take or apportioning and includes in vivo admin at least theoretically may be formed from a precursor com istration, as well as administration directly to tissue ex vivo. pound. These derivatives may be combined with another mol Generally, compositions may be administered systemically ecule to produce or enhance the biological effect. The bio either orally, buccally, parenterally, topically, by inhalation or logical effect may include, for example, but is not limited to, insufflation (i.e., through the mouth or through the nose), or modulating amyloid peptide levels within a subject; modu rectally in dosage unit formulations containing conventional lating tau phosphorylation levels within a Subject; decreasing nontoxic pharmaceutically acceptable carriers, adjuvants, amyloid peptide levels within a Subject; decreasing tau phos and vehicles as desired, or may be locally administered by phorylation levels within a subject, and the like. means such as, but not limited to, injection, implantation, 0041. The term “antagonist as used herein refers to a grafting, topical application, or parenterally. Substance that counteracts the effects of another Substance. 0035. The terms “subject” or “individual” or “patient” are The term "agonist’ as used herein refers to a chemical sub used interchangeably to refer to a member of an animal spe stance capable of activating a receptor to induce a full or cies of mammalian origin, including humans. partial pharmacological response. The term “blocker as used 0036. The phrase “a subject having a progressive cognitive herein refers to a substance that inhibits the physiological disease' as used herein refers to a subject who presents with action of another Substance. diagnostic markers and/or symptoms associated with a pro 0042. The term “leptin agonist” refers to a compound gressive cognitive disease. A progressive cognitive disease is capable of activating the leptin receptor and/or downstream usually diagnosed clinically from the patient history, collat effectors and of modulating amyloid peptide levels or tau eral history from relatives, and clinical observations, based on phosphorylation in a Subject. Such effectors may include, for the presence of characteristic neurological and neuropsycho example, but are not limited to, AMP-dependent protein logical features and the absence of alternative conditions. kinase (AMPK) and sterol regulatory element binding pro These criteria require that the presence of cognitive impair teins (“SREBP). ment, and a Suspected dementia syndrome, be confirmed by 0043. The leptin receptor (OB-R), a member of the class I neuropsychological testing. Advanced medical imaging with cytokine receptor Superfamily, has at least six isoforms as a computed tomography (CT) or magnetic resonance imaging result of alternative splicing. As used herein the term “iso (MRI), and with single photon emission computed tomogra form' refers to a version of a protein that has the same func phy (SPECT) or positron emission tomography (PET) may be tion as another protein but that has some Small difference(s) in used to help exclude other cerebral pathology or subtypes of its sequence. All isoforms of OB-R share an identical extra dementia. Assessment of intellectual functioning including cellular ligand-binding domain. Leptin's functional receptor memory testing can further characterize the state of the dis (OB-Rb), the b isoform, is expressed not only in the hypo ease. A histopathologic confirmation including a microscopic thalamus, where it regulates energy homeostasis and neu examination of brain tissue may be required for a definitive roendocrine function, but also in other brain regions and in the diagnosis. For AD, eight cognitive domains are most com periphery, including all cell types of innate and adaptive monly impaired: memory, language, perceptual skills, atten immunity. The full-length bisoform (OB-Rb) lacks intrinsic tion, constructive abilities, orientation, problem solving and tyrosine kinase activity and is involved in several downstream functional abilities. These domains are equivalent to the signal transduction pathways. NINCDS-ADRDA Alzheimer's Criteria as listed in the Diag 0044) The terms “therapeutically effective amount', an nostic and Statistical Manual of Mental Disorders (DSM-IV “amount effective', or “pharmaceutically effective amount TR) published by the American Psychiatric Association (in of one or more of the active agents are used interchangeably corporated in its entirety herein by reference). to refer to an amount that is sufficient to provide the intended 0037. A subject at risk of having a progressive cognitive benefit of treatment. An effective amount of the active agents disease is one who has one or more predisposing factors to the that can be employed according to the described invention development of a progressive cognitive disease. generally ranges from generally about 0.01 mg/kg body US 2009/029 1894 A1 Nov. 26, 2009 weight to about 100 g/kg body weight. However, dosage modulating amount is from about 0.01 mg/kg body weight to levels are based on a variety of factors, including the type of about 55 g/kg body weight. According to another embodi injury, the age, weight, sex, medical condition of the patient, ment, the phosphorylated tau accumulation modulating the severity of the condition, the route of administration, and amount is from about 0.01 mg/kg body weight to about 50 the particular active agent employed. Thus the dosage regi g/kg body weight. According to another embodiment, the men may vary widely, but can be determined routinely by a phosphorylated tau accumulation modulating amount is from physician using standard methods. Additionally, the terms about 0.01 mg/kg body weight to about 45 g/kg body weight. “therapeutically effective amounts” and “pharmaceutically According to another embodiment, the phosphorylated tau effective amounts include prophylactic or preventative accumulation modulating amount is from about 0.01 mg/kg amounts of the compositions of the described invention. In body weight to about 40 g/kg body weight. According to prophylactic or preventative applications of the described another embodiment, the phosphorylated tau accumulation invention, pharmaceutical compositions or medicaments are modulating amount is from about 0.01 mg/kg body weight to administered to a patient Susceptible to, or otherwise at risk about 35 g/kg body weight. According to another embodi of a disease, disorder or condition resulting from accumula ment, the phosphorylated tau accumulation modulating tion of anamyloid peptide in an amount Sufficient to eliminate amount is from about 0.01 mg/kg body weight to about 30 or reduce the risk, lessen the severity, or delay the onset of the g/kg body weight. According to another embodiment, the disease, disorder or condition, including biochemical, histo phosphorylated tau accumulation modulating amount is from logic and/or behavioral symptoms of the disease, disorder or about 0.01 mg/kg body weight to about 25 g/kg body weight. condition, its complications, and intermediate pathological According to another embodiment, the phosphorylated tau phenotypes presenting during development of the disease, accumulation modulating amount is from about 0.01 mg/kg disorder or condition. body weight to about 20 g/kg body weight. According to 0045. The term "phosphorylated tau accumulation modu another embodiment, the phosphorylated tau accumulation lating amount’ as used herein refers to atherapeutically effec modulating amount is from about 0.01 mg/kg body weight to tive amount of a leptin composition that modulates the phos about 15 g/kg body weight. According to another embodi phorylation of tau protein. A phosphorylated tau ment, the phosphorylated tau accumulation modulating accumulation-modulating amount includes prophylactic or amount is from about 0.01 mg/kg body weight to about 10 preventative amounts of the compositions of the described g/kg body weight. According to another embodiment, the invention. phosphorylated tau accumulation modulating amount is from 0046. The term “cognitive function enhancing amount’ as about 0.01 mg/kg body weight to about 5 g/kg body weight. used herein refers to a therapeutically effective amount of a According to another embodiment, the phosphorylated tau leptin composition (i.e., dose and frequency of administra accumulation modulating amount is from about 0.01 mg/kg tion) that modulates mental processes of perception, memory, body weight to about 4 g/kg body weight. According to judgment or reasoning and thereby adds to, improves, or another embodiment, the phosphorylated tau accumulation increases mental performance in a subject as compared to a modulating amount is from about 0.01 mg/kg body weight to Subject that has not been administered a cognitive-function about 3 g/kg body weight. According to another embodiment, enhancing amount of a composition or material. the phosphorylated tau accumulation modulating amount is 0047. A cognitive function enhancing amount is from from about 0.01 mg/kg body weight to about 2 g/kg body about 0.01 mg/kg body weight to about 100 g/kg body weight. weight. According to another embodiment, the phosphory 0048. According to another embodiment, the phosphory lated tau accumulation modulating amount is from about 0.01 lated tau accumulation modulating amount is from about 0.01 mg/kg body weight to about 1 g/kg body weight. According to mg/kg body weight to about 100 g/kg body weight. Accord another embodiment, the phosphorylated tau accumulation ing to another embodiment, the phosphorylated tau accumu modulating amount is from about 0.01 mg/kg body weight to lation modulating amount is from about 0.01 mg/kg body about 500 mg/kg body weight. According to another embodi weight to about 95 g/kg body weight. According to another ment, the phosphorylated tau accumulation modulating embodiment, the phosphorylated tau accumulation modulat amount is from about 0.01 mg/kg body weight to about 250 ing amount is from about 0.01 mg/kg body weight to about 90 mg/kg body weight. According to another embodiment, the g/kg body weight. According to another embodiment, the phosphorylated tau accumulation modulating amount is from phosphorylated tau accumulation modulating amount is from about 0.01 mg/kg body weight to about 100 mg/kg body about 0.01 mg/kg body weight to about 85 g/kg body weight. weight. According to another embodiment, the phosphory According to another embodiment, the phosphorylated tau lated tau accumulation modulating amount is from about 0.01 accumulation modulating amount is from about 0.01 mg/kg mg/kg body weight to about 50 mg/kg body weight. Accord body weight to about 80 g/kg body weight. According to ing to another embodiment, the phosphorylated tau accumu another embodiment, the phosphorylated tau accumulation lation modulating amount is from about 0.01 mg/kg body modulating amount is from about 0.01 mg/kg body weight to weight to about 25 mg/kg body weight. According to another about 75 g/kg body weight. According to another embodi embodiment, the phosphorylated tau accumulation modulat ment, the phosphorylated tau accumulation modulating ing amount is from about 0.01 mg/kg body weight to about 10 amount is from about 0.01 mg/kg body weight to about 70 mg/kg body weight. According to another embodiment, the g/kg body weight. According to another embodiment, the phosphorylated tau accumulation modulating amount is from phosphorylated tau accumulation modulating amount is from about 0.01 mg/kg body weight to about 5 mg/kg body weight. about 0.01 mg/kg body weight to about 65 g/kg body weight. According to another embodiment, the phosphorylated tau According to another embodiment, the phosphorylated tau accumulation modulating amount is from about 0.01 mg/kg accumulation modulating amount is from about 0.01 mg/kg body weight to about 1 mg/kg body weight. body weight to about 60 g/kg body weight. According to 0049. The term “therapeutic agent” as used herein refers to another embodiment, the phosphorylated tau accumulation a drug, molecule, nucleic acid, protein, composition or other US 2009/029 1894 A1 Nov. 26, 2009 substance that provides a therapeutic effect. The term be longer. The therapeutic agents may be a leptin antagonist, “active' as used herein refers to the ingredient, component or a leptin blocker, a leptin blocker, or an leptin antagonist, or constituent of the compositions of the present invention combinations thereof. responsible for the intended therapeutic effect. The terms 0055 According to another embodiment, the leptin com “therapeutic agent” and “active agent” are used interchange position and/or the first composition further comprises a sec ably herein. The active agent may be a therapeutically effec ond therapeutic agent. According to Some Such embodiments, tive amount of at least one of a leptin, a leptin mimic, a leptin the second therapeutic agent is an antibiotic agent. According derivative, or a leptin agonist or a pharmaceutically accept to some Such embodiments, the second therapeutic agent is an able salt thereof anti-fungal agent. According to some such embodiments, the second therapeutic agent is an anti-viral agent. According to 0050. The term “therapeutic component” as used herein Some such embodiments, the second therapeutic agent is an refers to a therapeutically effective dosage (i.e., dose and anti-protozoal agent. According to some Such embodiments, frequency of administration) that eliminates, reduces, or pre the second therapeutic agent is a steroidal anti-inflammatory vents the progression of a particular disease manifestation in agent. According to some Such embodiments, the second a percentage of a population. An example of a commonly therapeutic agent is a non-steroidal anti-inflammatory agent. used therapeutic component is the ED50, which describes the According to Some such embodiments, the second therapeu dose in a particular dosage that is therapeutically effective for tic agent is an anti-oxidant agent. According to Some Such a particular disease manifestation in 50% of a population. embodiments, the second therapeutic agent is a hormone. 0051. The term “therapeutic effect” as used herein refers According to Some such embodiments, the second therapeu to a consequence of treatment, the results of which are judged tic agent is a vitamin. According to Some Such embodiments, to be desirable and beneficial. A therapeutic effect may the second therapeutic agent is an antihistamine agent. include, directly or indirectly, the arrest, reduction, or elimi According to Some such embodiments, the second therapeu nation of a disease manifestation. A therapeutic effect also tic agent is a chemotherapeutic agent. may include, directly or indirectly, the arrest reduction or 0056. The term “antibiotic agent as used herein means elimination of the progression of a disease manifestation. any of a group of chemical Substances having the capacity to inhibit the growth of, or to destroy bacteria, and other micro 0052. The term “drug as used herein refers to a therapeu organisms, used chiefly in the treatment of infectious dis tic agent or any Substance, other than food, used in the pre eases. Examples of antibiotic agents include, but are not vention, diagnosis, alleviation, treatment, or cure of disease. limited to, Penicillin G. Methicillin; Nafcillin: Oxacillin; 0053. The compositions described herein are isolated mol Cloxacillin; Dicloxacillin; Ampicillin; Amoxicillin; Ticarcil ecules. An "isolated molecule' is a molecule that is substan lin; Carbenicillin: Mezlocillin; AZlocillin; Piperacillin: Imi tially pure and is free of other substances with which it is penem: Aztreonam; Cephalothin: Cefaclor; Cefoxitin: ordinarily found in nature or in Vivo systems to an extent Cefuroxime; Cefonicid; Cefinetazole; Cefotetan: Cefprozil; practical and appropriate for its intended use. In particular, Loracarbef Cefetamet; CefoperaZone; Cefotaxime; Cefti the compositions are sufficiently pure and are sufficiently free Zoxime; Ceftriaxone; Ceftazidime; Cefepime; Cefixime; from other biological constituents of host cells so as to be Cefpodoxime; Cefsulodin; Fleroxacin; Nalidixic acid; Nor useful in, for example, producing pharmaceutical prepara floxacin: Ciprofloxacin; Ofloxacin; Enoxacin; Lomefloxa tions or sequencing if the composition is a nucleic acid, cin; Cinoxacin; Doxycycline; Minocycline; Tetracycline; peptide, or polysaccharide. Because compositions may be Amikacin; Gentamicin; Kanamycin; Netilmicin; Tobramy admixed with a pharmaceutically-acceptable carrier in a cin; Streptomycin; Azithromycin; Clarithromycin; Erythro pharmaceutical preparation, the compositions may comprise mycin; Erythromycin estolate ; Erythromycin ethyl Succi only a small percentage by weight of the preparation. The nate; Erythromycin glucoheptonate; Erythromycin composition is nonetheless Substantially pure in that it has lactobionate; Erythromycin Stearate; Vancomycin; Teicopla been substantially separated from the substances with which nin; Chloramphenicol; Clindamycin; Trimethoprim; Sul it may be associated in living systems or during synthesis. As famethoxazole; Nitrofurantoin; Rifampin; Mupirocin; Met used herein, the term “substantially pure' refers purity of at ronidazole; Cephalexin; Roxithromycin; least 75%, at least 80%, at least 85%, at least 90%, at least Co-amoxiclavuanate; combinations of Piperacillin and TaZo 95% or at least 99% pure as determined by an analytical bactam; and their various salts, acids, bases, and other deriva protocol. Such protocols may include, for example, but are tives. Anti-bacterial antibiotic agents include, but are not not limited to, FACS, HPLC, gel electrophoresis, chromatog limited to, penicillins, cephalosporins, carbacephems, cepha raphy, and the like. mycins, carbapenems, monobactams, aminoglycosides, gly 0054 The leptin composition and/or the first composition copeptides, quinolones, tetracyclines, macrollides, and fluo may be combined with other therapeutic agents and admin roquinolones. istered locally. The leptin composition and/or first composi 0057 The term “anti-fungal agent” as used herein means tion and other therapeutic agent(s) may be administered any of a group of chemical Substances having the capacity to simultaneously or sequentially. When the other therapeutic inhibit the growth of or to destroy fungi. Anti-fungal agents agents are administered simultaneously, they can be admin include but are not limited to Amphotericin B, Candicidin, istered in the same or separate formulations, but are admin Dermostatin, Filipin, Fungichromin, Hachimycin, Hamycin, istered at the same time. The other therapeutic agents are Lucensomycin, Mepartricin, Natamycin, Nystatin, Pecilocin, administered sequentially with one another and with leptin Perimycin, AZaserine, Griseofulvin, Oligomycins, Neomy composition and/or first composition when the administra cin, Pyrrolnitrin, Siccanin, Tubercidin, Viridin, Butenafine, tion of the other therapeutic agents and the inhibitor is tem Naftifine, Terbinafine, Bifonazole, Butoconazole, Chlordan porally separated. The separation in time between the admin toin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, istration of these agents may be a matter of minutes or it may Enilconazole, Fenticonazole, Flutrimazole, Isoconazole, US 2009/029 1894 A1 Nov. 26, 2009

Ketoconazole, Lanoconazole, Miconazole, Omoconazole, text of the present invention include, without limitation, oxi Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, Tol cams, such as piroXicam, isoxicam, tenoxicam, Sudoxicam, ciclate, Tolindate, Tolnaftate, Fluconawle, Itraconazole, and CP-14.304; disalcid, benorylate, trilisate, safapryn, sol Saperconazole, Terconazole, Acrisorcin, Amorolfine, Biphe prin, diflunisal, and fendosal; acetic acid derivatives, such as namine, Bromosalicylchloranilide, Buclosamide, Calcium diclofenac, fenclofenac, indomethacin, Sulindac, tolmetin, Propionate, Chlorphenesin, Ciclopirox, Cloxyquin, Coparaf isoxepac, furofenac, tiopinac, Zidometacin, acematacin, fen finate, Diamthazole. Exalamide, Flucytosine, Halethazole, tiazac, Zomepirac, clindanac, oxepinac, felbinac, and ketoro Hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propi lac, fenamates, such as mefenamic, meclofenamic, flufe onic Acid, Pyrithione, Salicylanilide, Sodium Propionate, namic, niflumic, and tolfenamic acids; propionic acid Sulbentine, Tenonitrozole, Triacetin, Ujothion, Undecylenic derivatives, such as ibuprofen, naproxen, benoxaprofen, flur Acid, and Zinc Propionate. biprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pir 0058. The term “anti-viral agent” as used herein means profen, carprofen, oxaprozin, pranoprofen, miroprofen, tioX any of a group of chemical Substances having the capacity to aprofen, Suprofen, alminoprofen, and tiaprofenic; pyrazoles, inhibit the replication of or to destroy viruses used chiefly in Such as phenylbutaZone, oxyphenbutaZone, feprazone, aza the treatment of viral diseases. Anti-viral agents include, but propaZone, and trimethaZone. Mixtures of these non-steroidal are not limited to, Acyclovir, Cidofovir, Cytarabine, anti-inflammatory agents may also be employed, as well as Dideoxyadenosine, Didanosine, Edoxudine, Famciclovir, the dermatologically acceptable salts and esters of these Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, agents. For example, etofenamate, a flufenamic acid deriva Lamivudine, MADU, Penciclovir, Sorivudine, Stavudine, tive, is particularly useful for topical application. Trifluridine, Valacyclovir, Vidarabine, Zalcitabine, Zidovu 0062 “An anti-oxidant agent” as used herein refers to a dine, Acemannan, Acetylleucine, Amantadine, Amidinomy substance that inhibits oxidation or reactions promoted by cin, Delavirdine, Foscamet, Indinavir, Interferons (e.g., IFN oxygen or peroxides. Non-limiting examples of anti-oxidants alpha), Kethoxal, Lysozyme, MethisaZone, Moroxydine, that are usable in the context of the present invention include Nevirapine, Podophyllotoxin, Ribavirin, Rimantadine, ascorbic acid (vitamin C) and its salts, ascorbyl esters offatty Ritonavir2, Saquinavir, Stailimycin, Statolon, Tromantadine, acids, ascorbic acid derivatives (e.g., magnesium ascorbyl Zidovudine (AZT) and Xenazoic Acid. phosphate, Sodium ascorbyl phosphate, ascorbyl Sorbate), 0059. The term “anti-protozoal agent” as used herein tocopherol (vitamin E), tocopherol sorbate, tocopherol means any of a group of chemical Substances having the acetate, otheresters oftocopherol, butylated hydroxybenzoic capacity to inhibit the growth of or to destroy protozoans used acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman chiefly in the treatment of protozoal diseases. Examples of 2-carboxylic acid (commercially available under the trade antiprotozoal agents, without limitation include name TroloXR), gallic acid and its alkyl esters, especially pyrimethamine (DaraprimR) sulfadiazine, and Leucovorin. propyl gallate, uric acid and its salts and alkyl esters, Sorbic 0060 “Steroidal anti-inflammatory agent', as used herein, acid and its salts, lipoic acid, amines (e.g., N,N-diethylhy refer to any one of numerous compounds containing a 17-car droxylamine, amino-guanidine), Sulfhydryl compounds bon 4-ring system and includes the Sterols, various hormones (e.g., glutathione), dihydroxy fumaric acid and its salts, gly (as anabolic steroids), and glycosides. Representative cine pidolate, arginine pilolate, nordihydroguaiaretic acid, examples of steroidal anti-inflammatory drugs include, with bioflavonoids, curcumin, lysine, methionine, proline, Super out limitation, corticosteroids such as hydrocortisone, oxide dismutase, silymarin, tea extracts, grape skin/seed hydroxyltriamcinolone, alpha-methyl dexamethasone, dex extracts, melanin, and rosemary extracts. amethasone-phosphate, beclomethasone dipropionates, clo 0063 “Chemotherapeutic agent” refers to chemicals use betasol Valerate, desonide, desoxymethasone, desoxycorti ful in the treatment or control of a disease. Non-limiting costerone acetate, dexamethasone, dichlorisone, diflorasone examples of chemotherapeutic agents usable in context of the diacetate, diflucortolone Valerate, fluadrenolone, fluclorolone present invention include daunorubicin, doxorubicin, idaru acetonide, fludrocortisone, flumethasone pivalate, fluosi bicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, eto nolone acetonide, fluocinonide, flucortine butylesters, fluo poside, teniposide, vinblastine, Vincristine, mitomycin C, cortolone, fluprednidene (fluprednylidene) acetate, fluran 5-FU, paclitaxel, docetaxel, actinomycin D, colchicine, topo drenolone, halcinonide, hydrocortisone acetate, tecan, irinotecan, gemcitabine cyclosporin, Verapamil, Val hydrocortisone butyrate, methylprednisolone, triamcinolone spodor, probenecid, MK571, GF120918, LY335979, birico acetonide, cortisone, cortodoxone, flucetonide, fludrocorti dar, terfenadine, quinidine, pervilleine A and XR9576. Sone, difluorosone diacetate, fluradrenolone, fludrocortisone, 0064 Antihistamine agent” as used herein refers to any of difluroSone diacetate, fluradrenolone acetonide, medrysone, various compounds that counteract histamine in the body and amcinafel, amcinafide, betamethasone and the balance of its that are used for treating allergic reactions (such as hay fever) esters, chloroprednisone, chlorprednisone acetate, clocorte and cold symptoms. Non-limiting examples of antihista lone, clescinolone, dichlorisone, diflurprednate, flucloronide, mines usable in context of the present invention include chlo flunisolide, fluoromethalone, fluperolone, fluprednisolone, rpheniramine, brompheniramine, dexchlorpheniramine, tri hydrocortisone Valerate, hydrocortisone cyclopentylpropi polidine, clemastine, diphenhydramine, promethazine, onate, hydrocortamate, meprednisone, paramethasone, pred piperazines, piperidines, astemizole, loratadine and terfena nisolone, prednisone, beclomethasone dipropionate, triamci dine. nolone, and mixtures thereof. 0065 “Vitamin' as used herein, refers to any of various 0061 “Non-steroidal anti-inflammatory agents' refers to organic Substances essential in minute quantities to the nutri a large group of agents that are aspirin-like in their action, tion of most animals act especially as coenzymes and precur including ibuprofen (Advil)(R), naproxen sodium (Aleve).(R), sors of coenzymes in the regulation of metabolic processes. and acetaminophen (Tylenol).R. Additional examples of non Non-limiting examples of vitamins usable in context of the steroidal anti-inflammatory agents that are usable in the con present invention include vitamin A and its analogs and US 2009/029 1894 A1 Nov. 26, 2009

derivatives: retinol, retinal, retinyl palmitate, retinoic acid, comprises a leptin blocker, or a pharmaceutically acceptable tretinoin, iso-tretinoin (known collectively as retinoids), Vita salt thereof. According to another embodiment, the leptin min E (tocopherol and its derivatives), vitamin C (L-ascorbic composition comprises a mimic of a leptin blocker, or a acid and its esters and other derivatives), vitamin B (niaci pharmaceutically acceptable salt thereof. According to namide and its derivatives), alpha hydroxy acids (such as another embodiment, the leptin composition comprises a lep glycolic acid, lactic acid, tartaric acid, malic acid, citric acid, tin antagonist, or a pharmaceutically acceptable Salt thereof. etc.) and beta hydroxy acids (such as Salicylic acid and the According to another embodiment, the leptin composition like). comprises an AMP-dependent protein kinase inhibitor. 0.066 “Hormone' as used herein refers to natural sub 0071. According to another embodiment, the leptin com stances produced by organs of the body that travel by blood to position further comprises a second therapeutic agent. trigger activity in other locations or their synthetic analogs. According to Some such embodiments, the second therapeu Suitable hormones for use in the context of the present inven tic agent is an antibiotic. According to some Such embodi tion include, but are not limited to, any hormone produced by ments, the second therapeutic agent is an anti-fungal agent. neurosecretory cells, including gonadotropin releasing hor According to Some such embodiments, the second therapeu mone (GnRH), corticotropin releasing hormone (CRH), thy tic agent is an anti-viral agent. According to Some Such rotropin releasing hormone (TRH), prolactin inhibiting hor embodiments, the second therapeutic agent is an anti-proto mone (dopamine) and orexin (hypocretin), as well as Zoal agent. According to Some such embodiments, the second recombinant hormones, meaning hormones produced by a therapeutic agent is a non-steroidal anti-inflammatory agent. process using DNA engineered to contain sequences that According to Some such embodiments, the second therapeu normally would not occur together and introducing that DNA tic agent is an anti-oxidant. According to Some Such embodi into the cells of a host. ments, the second therapeutic agent is a steroidal anti-inflam 0067 Neurofibrillary tangles (“NFT) generally refer to matory agent. According to Some Such embodiments, the aggregates of the microtubule-associated protein “tau”. second therapeutic agent is a hormone. According to some which have become hyperphosphorylated and accumulate Such embodiments, the second therapeutic agent is a vitamin. inside the cells themselves. According to Some such embodiments, the second therapeu 0068 According to one embodiment, the progressive cog tic agent is an antihistamine agent. According to some Such nitive disorder comprises accumulation of neurofibrillary embodiments, the second therapeutic agent is an chemothera tangles in brain. According to another embodiment, the pro peutic agent. gressive cognitive disorder is Alzheimer's Disease. Accord ing to another embodiment, progressive cognitive disorder is Compositions progressive Supranuclear palsy. According to another 0072 The compositions are delivered in therapeutically embodiment, progressive cognitive disorder is dementia. effective amounts. Combined with the teachings provided According to another embodiment, progressive cognitive dis herein, by choosing among the various active compounds and order is dementia pugilistica. According to another embodi weighing factors such as potency, relative bioavailability, ment, progressive cognitive disorderis Creutzfeldt-Jakob dis patient body weight, severity of adverse side-effects and pre ease. According to another embodiment, progressive ferred mode of administration, an effective prophylactic or cognitive disorder is frontotemporal dementia. According to therapeutic treatment regimen may be planned which does another embodiment, progressive cognitive disorder is Pick's not cause substantial toxicity and yet is effective to treat the disease. According to another embodiment, progressive cog particular subject. The effective amount for any particular nitive disorder is FTDP-17 (parkinsonism) corticobasal application may vary depending on Such factors as the disease degeneration. According to another aspect, the present inven or condition being treated, the particular therapeutically tion provides a method of improving resilience of cognitive active leptin, leptin mimic, leptin agonist, leptin derivative function in a subject in need thereof, the method comprising peptide, leptin blocker and/or leptin antagonist, or combina the step of (a) administering to the Subject a composition tions thereof, being administered, the size of the Subject, or comprising: (i) a cognitive function-enhancing amount of a the severity of the disease or condition. One of ordinary skill leptin composition; and (ii) a pharmaceutically acceptable in the art may determine empirically the effective amount of carrier; and (b) modulating accumulation of phosphorylated a particular leptin composition and/or other therapeutic agent tau in cerebrospinal fluid of the subject. without necessitating undue experimentation. It generally is 0069. The term “resilience' as used herein refers to the preferred that a maximum dose be used, that is, the highest ability to return to the original form, position, or function after safe dose according to Some medical judgment. "Dose” and or during an illness, condition, disease, syndrome or disorder. “dosage' are used interchangeably herein. 0070 According to one embodiment of the method, the 0073 For any compound described herein the therapeuti leptin composition comprises a leptin, or a pharmaceutically cally effective amount initially may be determined from pre acceptable salt thereof. According to another embodiment, liminary in vitro studies and/or animal models. A therapeuti the leptin composition comprises a leptin mimic, or a phar cally effective dose may also be determined from human data maceutically acceptable salt thereof. According to another for a therapeutically active leptin, a leptin mimic, a leptin embodiment, the leptin composition comprises a leptin agonist, a leptin derivative peptide, a leptin blocker and/or a derivative, or a pharmaceutically acceptable salt thereof. leptin antagonist, or combinations thereof, which have been According to another embodiment, the leptin composition tested in humans and for compounds which are known to comprises an AMP-dependent protein kinase activator, or a exhibit similar pharmacological activities, such as other pharmaceutically acceptable salt thereof. According to related active agents. The applied dose may be adjusted based another embodiment, the leptin composition comprises a lep on the relative bioavailability and potency of the administered tin agonist, or a pharmaceutically acceptable salt thereof. compound or composition. Adjusting the dose to achieve According to another embodiment, the leptin composition maximal efficacy based on the methods described above and US 2009/029 1894 A1 Nov. 26, 2009

other methods as are well-known in the art is well within the or soft gelatin capsules wherein the active ingredient(s) is capabilities of the ordinarily skilled artisan. (are) mixed with water oran oil medium, for example, peanut 0074 The formulations of a first composition, a leptin oil, liquid paraffin, or olive oil. composition, a therapeutically active leptin, a leptin mimic, a 007.9 The compositions of the present invention may be leptin agonist, a leptin derivative peptide, a leptin blocker formulated as aqueous Suspensions wherein the active ingre and/or a leptin antagonist, or combinations thereof, may be dient(s) is (are) in admixture with excipients suitable for the administered in pharmaceutically acceptable Solutions, manufacture of aqueous Suspensions. Such excipients are which may routinely contain pharmaceutically acceptable Suspending agents, for example, Sodium carboxymethylcel concentrations of salt, buffering agents, preservatives, com lulose, methylcellulose, hydroxy-propylmethylcellulose, patible carriers, adjuvants, and optionally other therapeutic Sodium alginate, polyvinylpyrrolidone, gum tragacanth, and ingredients. gum acacia; dispersing or wetting agents may be a naturally 0075 For use in therapy, an effective amount of the first occurring phosphatide such as lecithin, or condensation prod composition, and/or a leptin composition, a therapeutically ucts of an alkylene oxide with fatty acids, for example, poly active leptin, a leptin mimic, a leptin agonist, a leptin deriva oxyethylene Stearate, or condensation products of ethylene tive peptide, a leptin blocker and/or a leptin antagonist, or oxide with long chain aliphatic alcohols, for example, hepta combinations thereof, may be administered to a subject by decaethyl-eneoxycetanol, or condensation products of ethyl any mode that delivers the leptin composition and/or the first ene oxide with partial esters derived from fatty acids and a composition to the desired surface. Administering the phar hexitol Such as polyoxyethylene Sorbitol monooleate, or con maceutical composition may be accomplished by any means densation products of ethylene oxide with partial esters known to the skilled artisan. Routes of administration derived from fatty acids and hexitol anhydrides, for example include, but are not limited to, intrathecal, intra-arterial, polyethylene Sorbitan monooleate. The aqueous Suspensions parenteral (e.g. intravenous), or intramuscular, orally, buc also may contain one or more coloring agents, one or more cally, intranasally, rectally, or topically. flavoring agents, and one or more Sweetening agents, such as 0076. The inhibitors and other therapeutics may be deliv Sucrose or saccharin. ered to a subject during Surgery to treat an underlying condi 0080 Compositions of the present invention may be for tion or side effect Such as Subarachnoid hemorrhage or mulated as oily Suspensions by Suspending the active ingre peripheral vasospasm or during intra-arterial procedures. dient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil. Such as liquid Oral Compositions paraffin. The oily Suspensions may contain a thickening 0077. The compositions of the present invention may be in agent, for example, beeswax, hard paraffin or cetyl alcohol. a form Suitable for oral use, for example, as tablets, troches, Sweetening agents, such as those set forth above, and flavor lozenges, aqueous or oily Suspensions, dispersible powders ing agents may be added to provide a palatable oral prepara or granules, emulsions, hard or soft capsules or syrups or tion. These compositions may be preserved by the addition of elixirs. As used herein, the terms "oral or “orally’ refer to the an antioxidant such as ascorbic acid. introduction into the body by mouth whereby absorption I0081 Compositions of the present invention may be for occurs in one or more of the following areas of the body: the mulated in the form of dispersible powders and granules mouth, stomach, Small intestine, lungs (also specifically Suitable for preparation of an aqueous Suspension by the referred to as inhalation), and the small blood vessels under addition of water. The active ingredient in Such powders and the tongue (also specifically referred to as Sublingually). granules is provided in admixture with a dispersing or wetting Compositions intended for oral use may be prepared accord agent, Suspending agent, and one or more preservatives. Suit ing to any known method, and Such compositions may con able dispersing or wetting agents and Suspending agents are tain one or more agents selected from the group consisting of exemplified by those already mentioned above. Additional Sweetening agents, flavoring agents, coloring agents, and pre excipients, for example, Sweetening, flavoring and coloring serving agents in order to provide pharmaceutically elegant agents, also may be present. and palatable preparations. Tablets may contain the active I0082. The compositions of the invention also may be in the ingredient(s) in admixture with non-toxic pharmaceutically form of an emulsion. An emulsion is a two-phase system acceptable excipients which are suitable for the manufacture prepared by combining two immiscible liquid carriers, one of of tablets. These excipients may be, for example, inert dilu which is disbursed uniformly throughout the other and con ents, such as calcium carbonate, sodium carbonate, lactose, sists of globules that have diameters equal to or greater than calcium phosphate or sodium phosphate; granulating and those of the largest colloidal particles. The globule size is disintegrating agents, for example, corn starch oralginic acid; critical and must be such that the system achieves maximum binding agents, for example, starch, gelatin or acacia; and stability. Usually, separation of the two phases will not occur lubricating agents, for example, magnesium Stearate, Stearic unless a third Substance, an emulsifying agent, is incorpo acid or talc. The tablets may be uncoated or they may be rated. Thus, a basic emulsion contains at least three compo coated by known techniques to delay disintegration and nents, the two immiscible liquid carriers and the emulsifying absorption in the gastrointestinal tract and thereby provide a agent, as well as the active ingredient. Most emulsions incor Sustained action over a longer period. For example, a time porate an aqueous phase into a non-aqueous phase (or vice delay material Such as glyceryl monostearate or glyceryl dis Versa). However, it is possible to prepare emulsions that are tearate may be employed. They also may be coated for con basically non-aqueous, for example, anionic and cationic Sur trolled release. factants of the non-aqueous immiscible system glycerin and 0078 Compositions of the present invention also may be olive oil. Thus, the compositions of the invention may be in formulated for oral use as hard gelatin capsules, where the the form of an oil-in-water emulsion. The oily phase may be active ingredient(s) is(are) mixed with an inert Solid diluent, a vegetable oil, for example, olive oil or arachis oil, or a for example, calcium carbonate, calcium phosphate or kaolin, mineral oil, for example a liquid paraffin, or a mixture thereof. US 2009/029 1894 A1 Nov. 26, 2009

Suitable emulsifying agents may be naturally-occurring priate oily injection Suspensions. Suitable lipophilic solvents gums, for example, gum acacia or gum tragacanth, naturally or vehicles include fatty oils such as sesame oil, or synthetic occurring phosphatides, for example Soybean, lecithin, and fatty acid esters, such as ethyl oleate or triglycerides, or esters or partial esters derived from fatty acids and hexitol liposomes. Aqueous injection Suspensions may contain Sub anhydrides, for example Sorbitan monooleate, and condensa stances which increase the viscosity of the Suspension, Such tion products of the partial esters with ethylene oxide, for as sodium carboxymethyl cellulose, Sorbitol, or dextran. example, polyoxyethylene Sorbitan monooleate. The emul Optionally, the Suspension also may contain Suitable stabiliz sions also may contain Sweetening and flavoring agents. ers or agents which increase the Solubility of the compounds 0083. The compositions of the invention also may be for to allow for the preparation of highly concentrated Solutions. mulated as syrups and elixirs. Syrups and elixirs may be Alternatively, the active compounds may be in powder form formulated with Sweetening agents, for example, glycerol, for constitution with a suitable vehicle, e.g., Sterile pyrogen propylene glycol, Sorbitol or Sucrose. Such formulations also free water, before use. may contain a demulcent, a preservative, and flavoring and I0087. The pharmaceutical compositions also may com coloring agents. Demulcents are protective agents employed prise Suitable Solid or gel phase carriers or excipients. primarily to alleviate irritation, particularly mucous mem Examples of Such carriers or excipients include, but are not branes or abraded (meaning torn or cut) tissues. A number of limited to, calcium carbonate, calcium phosphate, various chemical Substances possess demulcent properties. These Sugars, starches, cellulose derivatives, gelatin, and polymers Substances include the alginates, mucilages, gums, dextrins, Such as polyethylene glycols. starches, certain Sugars, and polymeric polyhydric glycols. I0088 Suitable liquid or solid pharmaceutical preparation Others include acacia, agar, benzoin, carbomer, gelatin, glyc forms are, for example, microencapsulated, and if appropri erin, hydroxyethyl cellulose, hydroxypropyl cellulose, ate, with one or more excipients, encochleated, coated onto hydroxypropyl methylcellulose, propylene glycol, Sodium microscopic gold particles, contained in liposomes, pellets alginate, tragacanth, hydrogels and the like. for implantation into the tissue, or dried onto an object to be rubbed into the tissue. Such pharmaceutical compositions Buccal Compositions also may be in the form of granules, beads, powders, tablets, 0084. For buccal administration, the compositions of the coated tablets, (micro)capsules, Suppositories, syrups, emul present invention may take the form of tablets or lozenges sions, Suspensions, creams, drops or preparations with pro formulated in a conventional manner. tracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disinte Parenteral Compositions grants, binders, coating agents, Swelling agents, lubricants, or solubilizers are customarily used as described above. The 0085. The compositions of the present invention may be in pharmaceutical compositions are suitable for use in a variety the form of a sterile injectable aqueous or oleaginous Suspen of drug delivery systems. For a brief review of methods for sion. The term “parenteral as used herein refers to introduc drug delivery, see Langer 1990 Science 249, 1527-1533, tion into the body by way of an injection (i.e., administration which is incorporated herein by reference. by injection), including, for example, Subcutaneously (i.e., an I0089. The first composition and/or leptin composition, injection beneath the skin), intramuscularly (i.e., an injection therapeutically active leptin, leptin mimic, leptin agonist, into a muscle); intravenously (i.e., an injection into a vein), leptin derivative peptide, leptin blocker and/or leptin antago intrathecally (i.e., an injection into the space around the spinal nist, or combinations thereof, and optionally other therapeu cord), intrastemal injection, or infusion techniques. A tics may be administered per se (neat) or in the form of a parenterally administered composition of the present inven pharmaceutically acceptable salt. Other therapeutics may tion is delivered using a needle, e.g., a Surgical needle. The include, but are not limited to, an antibiotic agent, an anti term "surgical needle' as used herein, refers to any needle fungal agent, an anti-Viral agent, an anti-protozoal agent, a adapted for delivery of fluid (i.e., capable of flow) composi steroidal anti-inflammatory agent, a non-steroidal anti-in tions of the present invention into a selected anatomical struc flammatory agent, an anti-oxidant agent, a hormone, a vita ture. Injectable preparations, such as sterile injectable aque min, an antihistamine agent, a chemotherapetic agent, or ous or oleaginous Suspensions, may be formulated according combinations thereof. When used in medicine the salts should to the known art using Suitable dispersing or wetting agents be pharmaceutically acceptable, but non-pharmaceutically and Suspending agents. acceptable salts may conveniently be used to prepare phar I0086. The first composition and/or leptin composition, maceutically acceptable salts thereof. Such salts include, but therapeutically active leptin, leptin mimic, leptin agonist, are not limited to, those prepared from the following acids: leptin derivative peptide, leptin blocker and/or leptin antago hydrochloric, hydrobromic, Sulphuric, nitric, phosphoric, nist, when it is desirable to deliver them locally, may be maleic, acetic, salicylic, p-toluene Sulphonic, tartaric, citric, formulated for parenteral administration by injection, e.g., by methane Sulphonic, formic, malonic, succinic, naphthalene bolus injection or continuous infusion. Formulations for 2-sulphonic, and benzene Sulphonic. Also, Such salts may be injection may be presented in unit dosage form, for example, prepared as alkaline metal or alkaline earth salts, such as in ampoules or in multi-dose containers, with an added pre Sodium, potassium or calcium salts of the carboxylic acid servative. The compositions may take Such forms as Suspen group. By “pharmaceutically acceptable salt' is meant those sions, Solutions or emulsions in oily or aqueous vehicles, and salts which are, within the scope of sound medical judgment, may contain formulatory agents such as Suspending, stabiliz Suitable for use in contact with the tissues of humans and ing and/or dispersing agents. Pharmaceutical formulations lower animals without undue toxicity, irritation, allergic for parenteral administration include aqueous Solutions of the response and the like and are commensurate with areasonable active compounds in water-soluble form. Additionally, Sus benefit/risk ratio. Pharmaceutically acceptable salts are well pensions of the active compounds may be prepared as appro known in the art. For example, P. H. Stahl, et al. describe US 2009/029 1894 A1 Nov. 26, 2009

pharmaceutically acceptable salts in detail in “Handbook of carriers or finely divided solid carriers or both and then, if Pharmaceutical Salts: Properties, Selection, and Use' (Wiley necessary, shaping the product into the desired formulation. VCH, Zurich, Switzerland: 2002). The salts may be prepared 0091. The pharmaceutical agent or a pharmaceutically in situ during the final isolation and purification of the com acceptable ester, salt, Solvate or prodrug thereof may be pounds described within the present invention or separately mixed with other active materials that do not impair the by reacting a free base function with a Suitable organic acid. desired action, or with materials that supplement the desired Representative acid addition salts include, but are not limited action. Solutions or Suspensions used for parenteral, intrad to, acetate, adipate, alginate, citrate, aspartate, benzoate, ben ermal, Subcutaneous, intrathecal, or topical application may Zenesulfonate, bisulfate, butyrate, camphorate, camphorSu include, but are not limited to, for example, the following fonate, digluconate, glycerophosphate, hemisulfate, hep components: a sterile diluent such as water for injection, tanoate, hexanoate, fumarate, hydrochloride, hydrobromide, saline solution, fixed oils, polyethylene glycols, glycerine, hydroiodide, 2-hydroxyethansulfonate(isethionate), lactate, propylene glycol or other synthetic solvents; antibacterial maleate, methanesulfonate, nicotinate, 2-naphthalene agents such as benzyl alcohol or methyl parabens; antioxi Sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl dants such as ascorbic acid or sodium bisulfite; chelating propionate, picrate, pivalate, propionate, Succinate, tartrate, agents such as ethylenediaminetetraacetic acid; buffers such thiocyanate, phosphate, glutamate, bicarbonate, p-toluene as acetates, citrates or phosphates and agents for the adjust Sulfonate and undecanoate. Also, the basic nitrogen-contain ment of tonicity such as sodium chloride or dextrose. The ing groups may be quaternized with Such agents as lower parental preparation may be enclosed in ampoules, dispos alkyl halides such as methyl, ethyl, propyl, and butyl chlo able syringes or multiple dose vials made of glass or plastic. rides, bromides and iodides; dialkyl sulfates like dimethyl, Administered intravenously, particular carriers are physi diethyl, dibutyl and diamyl Sulfates; long chain halides Such ological saline or phosphate buffered saline (PBS). as decyl, lauryl, myristyl and Stearyl chlorides, bromides and 0092 Pharmaceutical compositions for parenteral injec iodides: arylalkylhalides like benzyl and phenethyl bromides tion comprise pharmaceutically acceptable sterile aqueous or and others. Water or oil-soluble or dispersible products are nonaqueous Solutions, dispersions, Suspensions or emulsions thereby obtained. Examples of acids which may be employed and sterile powders for reconstitution into sterile injectable to form pharmaceutically acceptable acid addition salts Solutions or dispersions. Examples of Suitable aqueous and include Such inorganic acids as hydrochloric acid, hydrobro nonaqueous carriers, diluents, solvents or vehicles include mic acid, Sulphuric acid and phosphoric acid and Such organic water, ethanol, polyols (propylene glycol, polyethylene gly acids as Oxalic acid, maleic acid, Succinic acid and citric acid. col, glycerol, and the like), suitable mixtures thereof, veg Basic addition salts may be prepared in situ during the final etable oils (such as olive oil) and injectable organic esters isolation and purification of compounds described within the such as ethyl oleate. Proper fluidity may be maintained, for invention by reacting a carboxylic acid-containing moiety example, by the use of a coating Such as lecithin, by the with a suitable base such as the hydroxide, carbonate or maintenance of the required particle size in the case of dis bicarbonate of a pharmaceutically acceptable metal cation or persions, and by the use of Surfactants. with ammonia or an organic primary, secondary or tertiary 0093. These compositions may also contain adjuvants amine. Pharmaceutically acceptable salts include, but are not including preservative agents, wetting agents, emulsifying limited to, cations based on alkali metals or alkaline earth agents, and dispersing agents. Prevention of the action of metals such as lithium, Sodium, potassium, calcium, magne microorganisms may be ensured by various antibacterial and sium and aluminum salts and the like and nontoxic quaternary antifungal agents, for example, parabens, chlorobutanol, phe ammonia and amine cations including ammonium, tetram nol, sorbic acid, and the like. It may also be desirable to ethylammonium, tetraethylammonium, methylamine, dim include isotonic agents, for example, Sugars, sodium chloride ethylamine, trimethylamine, triethylamine, diethylamine, and the like. Prolonged absorption of the injectable pharma ethylamine and the like. Other representative organic amines ceutical form may be brought about by the use of agents useful for the formation of base addition salts include ethyl delaying absorption, for example, aluminum monostearate enediamine, ethanolamine, diethanolamine, piperidine, pip and gelatin. erazine and the like. Pharmaceutically acceptable salts also 0094 Suspensions, in addition to the active compounds, may be obtained using standard procedures well known in the may contain Suspending agents, as, for example, ethoxylated art, for example by reacting a sufficiently basic compound isostearyl alcohols, polyoxyethylene Sorbitol and Sorbitan Such as an amine with a suitable acid affording a physiologi esters, microcrystalline cellulose, aluminum metahydroxide, cally acceptable anion. Alkali metal (for example, Sodium, bentonite, agar-agar, tragacanth, and mixtures thereof. potassium or lithium) or alkaline earth metal (for example 0.095 Injectable depot forms are made by forming calcium or magnesium) salts of carboxylic acids also may be microencapsulated matrices of the drug in biodegradable made. polymers such as polylactide-polyglycolide. Depending 0090 The formulations may be presented conveniently in upon the ratio of drug to polymer and the nature of the par unit dosage form and may be prepared by any of the methods ticular polymer employed, the rate of drug release may be well known in the art of pharmacy. All methods include the controlled. Such long acting formulations may be formulated step of bringing into associationaleptin composition, a thera with suitable polymeric or hydrophobic materials (for peutically active leptin, a leptin mimic, a leptin agonist, a example as an emulsion in an acceptable oil) or ion exchange leptin derivative peptide, a leptin blocker and/or a leptin resins, or as sparingly soluble derivatives, for example, as a antagonist, or combinations thereof, or a pharmaceutically sparingly soluble salt. Examples of other biodegradable poly acceptable salt or solvate thereof (“active compound') with mers include poly(orthoesters) and poly(anhydrides). Depot the carrier which constitutes one or more accessory agents. In injectable formulations are also prepared by entrapping the general, the formulations are prepared by uniformly and inti drug in liposomes or microemulsions which are compatible mately bringing into association the active agent with liquid with body tissues. US 2009/029 1894 A1 Nov. 26, 2009

0096. The locally injectable formulations may be steril herein, including, but not limited to, an antibiotic agent, an ized, for example, by filtration through a bacterial-retaining anti-fungal agent, an anti-viral agent, an anti-protozoal agent, filter or by incorporating sterilizing agents in the form of a steroidal anti-inflammatory agent, a non-steroidal anti-in sterile solid compositions that may be dissolved or dispersed flammatory agent, an anti-oxidant agent, a hormone, a vita in sterile water or other sterile injectable medium just prior to min, an antihistamine agent, a chemotherapetic agent, or use. Injectable preparations, for example, sterile injectable combinations thereof. The particles may contain the thera aqueous or oleaginous Suspensions may be formulated peutic agent(s) in a core Surrounded by a coating. The thera according to the known art using Suitable dispersing or wet peutic agent(s) also may be dispersed throughout the par ting agents and Suspending agents. The sterile injectable ticles. The therapeutic agent(s) also may be adsorbed into the preparation also may be a sterile injectable solution, Suspen particles. The particles may be of any order release kinetics, sion or emulsion in a nontoxic, parenterally acceptable dilu including Zero order release, first order release, second order ent or solvent such as a solution in 1,3-butanediol. Among the release, delayed release, Sustained release, immediate acceptable vehicles and solvents that may be employed are release, etc., and any combination thereof. The particle may water, Ringer's solution, U.S.P. and isotonic sodium chloride include, in addition to the therapeutic agent(s), any of those Solution. In addition, Sterile, fixed oils conventionally are materials routinely used in the art of pharmacy and medicine, employed or as a solvent or Suspending medium. For this including, but not limited to, erodible, nonerodible, biode purpose any bland fixed oil may be employed including Syn gradable, or nonbiodegradable material or combinations thetic mono- or diglycerides. In addition, fatty acids such as thereof. The particles may be microcapsules that contain the oleic acid are used in the preparation of injectables. leptin composition, therapeutically active leptin, leptin 0097. Formulations for parenteral (including but not lim mimic, leptinagonist, leptin derivative peptide, leptin blocker ited to, Subcutaneous, intradermal, intramuscular, intrave and/or leptin antagonist, or combinations thereof, in a solu nous, intrathecal and intraarticular) administration include tion or in a semi-solid state. The particles may be of virtually aqueous and non-aqueous sterile injection Solutions that may any shape. contain anti-oxidants, buffers, bacteriostats and solutes, 0101 Both non-biodegradable and biodegradable poly which render the formulation isotonic with the blood of the meric materials may be used in the manufacture of particles intended recipient; and aqueous and non-aqueous sterile Sus for delivering the therapeutic agent(s). Such polymers may be pensions, which may include Suspending agents and thicken natural or synthetic polymers. The polymer is selected based ing agents. The formulations may be presented in unit-dose or on the period of time over which release is desired. Bioadhe multi-dose containers, for example sealed ampules and vials, sive polymers of particular interest include bioerodible and may be stored in a freeze-dried (lyophilized) condition hydrogels as described by Sawhney etal in Macromolecules requiring only the addition of the sterile liquid carrier, for (1993) 26, 581-587, the teachings of which are incorporated example, saline, water-for-injection, immediately prior to herein. These include polyhyaluronic acids, casein, gelatin, use. Extemporaneous injection Solutions and Suspensions glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, may be prepared from Sterile powders, granules and tablets of poly(methyl methacrylates), poly(ethyl methacrylates), poly the kind previously described. (butylmethacrylate), poly(isobutyl methacrylate), poly(hexy 0098. Another method of formulation of the compositions lmethacrylate), poly(isodecyl methacrylate), poly(lauryl described herein involves conjugating the compounds methacrylate), poly(phenyl methacrylate), poly(methyl acry described herein to a polymer that enhances aqueous solubil late), poly(isopropyl acrylate), poly(isobutyl acrylate), and ity. Examples of suitable polymers include but are not limited poly(octadecyl acrylate). to polyethylene glycol, poly-(d-glutamic acid), poly-(1- glutamic acid), poly-(1-glutamic acid), poly-(d-aspartic Insufflation Compositions acid), poly-(1-aspartic acid), poly-(1-aspartic acid) and 0102 The compositions of the present invention may be in copolymers thereof. Polyglutamic acids having molecular the form of a dispersible dry powder for delivery by inhalation weights between about 5,000 to about 100,000, with molecu or insufflation (either through the mouth or through the nose). lar weights between about 20,000 and about 80,000 may be Dry powder compositions may be prepared by processes used and with molecular weights between about 30,000 and known in the art, Such as lyophilization and jet milling, as about 60,000 may also be used. disclosed in International Patent Publication No. WO 0099 Suitable buffering agents include: acetic acid and a 91/16038 and as disclosed in U.S. Pat. No. 6,921,527, the salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid disclosures of which are incorporated by reference. Spray and a salt (0.5-2.5% w/v); and phosphoric acid and a salt drying, for example, is a process in which a homogeneous (0.8-2% w/v). Suitable preservatives include benzalkonium aqueous mixture of drug and the carrier is introduced via a chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); nozzle (e.g., a two fluid nozzle), spinning disc or an equiva parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% lent device into a hot gas stream to atomize the Solution to w/v). form fine droplets. The aqueous mixture may be a solution, 0100. The therapeutic agent(s), including the leptin com Suspension, slurry, or the like, but needs to be homogeneous position, therapeutically active leptin, leptin mimic, leptin to ensure uniform distribution of the components in the mix agonist, leptin derivative peptide, leptin blocker and/or leptin ture and ultimately the powdered composition. The solvent, antagonist, or combinations thereof, may be provided in par generally water, rapidly evaporates from the droplets produc ticles. The term “particles” as used herein refers to nano- or ing a fine dry powder having particles from about 1 um to 5 microparticles (or in some instances larger) that may contain um in diameter. The spray drying is done under conditions in whole or in part the leptin composition, therapeutically that result in a Substantially amorphous powder of homoge active leptin, leptin mimic, leptin agonist, leptin derivative neous constitution having a particle size that is respirable, a peptide, leptin blocker and/or leptin antagonist, or combina low moisture content and flow characteristics that allow for tions thereof, or the other therapeutic agent(s) as described ready aerosolization. Preferably the particle size of the result US 2009/029 1894 A1 Nov. 26, 2009

ing powder is such that more than about 98% of the mass is in invention are readily absorbed in the lungs without the need to particles having a diameter of about 10um or less with about employ penetration enhancers. 90% of the mass being in particles having a diameter less than 0107 The types of pharmaceutical excipients that are use 5um. Alternatively, about 95% of the mass will have particles ful as carriers for pulmonary delivery include stabilizers such with a diameterofless than 10um with about 80% of the mass as human serum albumin (HSA), bulking agents such as of the particles having a diameter of less than 5 Jum. Dry carbohydrates, amino acids and polypeptides; pH adjusters or powder compositions also may be prepared by lyophilization buffers; salts such as sodium chloride; and the like. These and jet milling, as disclosed in International Patent Publica carriers may be in a crystalline or amorphous form or may be tion No. WO 91/16038, the disclosure of which are incorpo a mixture of the two. rated by reference. 0.108 Bulking agents that are particularly valuable for pull monary delivery include compatible carbohydrates, polypep (0103) The term “dispersibility” or “dispersible” means a tides, amino acids or combinations thereof. Suitable carbo dry powder having a moisture content of less than about 10% hydrates include monosaccharides such as galactose, by weight (% w) water, usually below about 5% w and pref D-mannose, Sorbose, and the like; disaccharides, such as erably less than about 3% w; a particle size of about 1.0-5.0 lactose, trehalose, and the like; cyclodextrins, such as 2-hy um mass median diameter (MMD), usually 1.0–4.0 um droxypropyl-3-cyclodextrin; and polysaccharides, such as MMD, and preferably 1.0-3.0 um MMD; a delivered dose of raffinose, maltodextrins, dextrans, and the like; alditols. Such about >30%, usually >40%, preferably >50%, and most pre as mannitol. Xylitol, and the like. A preferred group of carbo ferred >60%; and anaerosol particle size distribution of about hydrates includes lactose, trehalose, raffinose, maltodextrins, 1.0-5.0 um mass median aerodynamic diameter (MMAD), and mannitol. Suitable polypeptides include aspartame. usually 1.5-4.5 um MMAD, and preferably 1.5-4.0 um Amino acids include alanine and glycine, with glycine being MMAD. Methods and compositions for improving dispers preferred. ibility are disclosed in U.S. application Ser. No. 08/423,568, 0109 Additives, which are minor components of the com filed Apr. 14, 1995, the disclosure of which is hereby incor position for pulmonary delivery, may be included for confor porated by reference. mational stability during spray drying and for improving 0104. The term “powder” means a composition that con dispersibility of the powder. These additives include hydro sists of finely dispersed solid particles that are free flowing phobic amino acids such as tryptophan, tyrosine, leucine, and capable of being readily dispersed in an inhalation device phenylalanine, and the like. and subsequently inhaled by a subject so that the particles 0110. For delivery by inhalation or insufflation, the com reach the lungs to permit penetration into the alveoli. Thus, position of the present invention is placed within a suitable the powder is said to be “respirable.” Preferably the average dosage receptacle in an amount Sufficient to provide a subject particle size is less than about 10 microns (Lm) in diameter with a unit dosage treatment. The dosage receptacle is one with a relatively uniform spheroidal shape distribution. More that fits within a suitable inhalation device to allow for the preferably the diameter is less than about 7.5 um and most aerosolization of the dry powder composition by dispersion preferably less than about 5.0 lum. Usually the particle size into a gas stream to form an aerosol and then capturing the distribution is between about 0.1 um and about 5 um in aerosol so produced in a chamber having a mouthpiece diameter, particularly about 0.3 um to about 5um. attached for Subsequent inhalation by a subject in need of 0105. The term “dry” means that the composition has a treatment. Such a dosage receptacle includes any container moisture content such that the particles are readily dispersible enclosing the composition known in the art Such as gelatin or in an inhalation device to form an aerosol. This moisture plastic capsules with a removable portion that allows a stream content is generally below about 10% by weight (% w) water, of gas (for example, air) to be directed into the container to usually below about 5% w and preferably less than about 3% disperse the dry powder composition. Such containers are W exemplified by those shown in U.S. Pat. No. 4,227,522; U.S. 0106 The amount of the pharmaceutically acceptable car Pat. No. 4,192,309; and U.S. Pat. No. 4,105,027. Suitable rier is that amount needed to provide the necessary stability, containers also include those used in conjunction with dispersibility, consistency and bulking characteristics to Glaxo's Ventolin R. Rotohaler brand powder inhaleror Fison's ensure a uniform pulmonary delivery of the composition to a Spinhaler R brand powder inhaler. Another suitable unit-dose subject in need thereof. Numerically the amount may be from container which provides a Superior moisture barrier is about 0.05% w to about 99.95% w, depending on the activity formed from an aluminum foil plastic laminate. The pharma of the drug being employed. Preferably about 5% w to about ceutical-based powder is filled by weight or by volume into 95% will be used. The carrier may be one or a combination of the depression in the formable foil and hermetically sealed two or more pharmaceutical excipients, but generally will be with a covering foil-plastic laminate. Such a container for use substantially free of any “penetration enhancers.” Penetration with a powder inhalation device is described in U.S. Pat. No. enhancers are surface active compounds which promote pen 4,778,054 and is used with Glaxo's Diskhaler (U.S. Pat. Nos. etration of a drug through a mucosal membrane or lining and 4,627,432;4,811,731; and 5,035,237). All of these references are proposed for use in intranasal, intrarectal, and intravaginal are incorporated herein by reference. drug formulations. Exemplary penetration enhancers include 0111. The compositions of the invention may be used in bile salts, e.g., taurocholate, glycocholate, and deoxycholate; the form of drops or sprays (e.g., a nasal spray, aerosol spray, fusidates, e.g., taurodehydrofusidate; and biocompatible or pump spray) or other vehicles for nasal administration detergents, e.g., Tweens, Laureth-9, and the like. The use of (intranasal delivery). Aerosol spray preparations can be con penetration enhancers informulations for the lungs, however, tained in a pressurized container with a Suitable propellant is generally undesirable because the epithelial blood barrier Such as a hydrocarbon propellant. Pump spray dispensers can in the lung can be adversely affected by such surface active dispense a metered dose or a dose having a specific particle or compounds. The dry powder compositions of the present droplet size. Any dispensing device can be arranged to dis US 2009/029 1894 A1 Nov. 26, 2009

pense only a single dose, or a multiplicity of doses. More compound(s) when mixed with it. The term “active' refers to generally, compositions of the invention, especially those the ingredient, component or constituent of the compositions formulated for intranasal administration, can also be provided of the present invention responsible for the intended thera as Solutions, Suspensions, or viscous compositions (e.g., gels, peutic effect. Carriers must be of sufficiently high purity and lotions, creams, or ointments). of sufficiently low toxicity to render them suitable for admin istration to the subject being treated. The carrier can be inert, Rectal Compositions or it can possess pharmaceutical benefits. 0112 The compositions of the present invention may be in 0117 The carrier can be liquid or solid and is selected with the form of suppositories for rectal administration of the the planned manner of administration in mind to provide for composition. “Rectal or “rectally as used herein refers to the desired bulk, consistency, etc., when combined with an introduction into the body through the rectum where absorp active and the other components of a given composition. tion occurs through the walls of the rectum. These composi Typical pharmaceutical carriers include, but are not limited tions can be prepared by mixing the drug with a suitable to, binding agents (including, but not limited to, pregelati nonirritating excipient such as cocoa butter and polyethylene nized maize starch, polyvinylpyrrolidone or hydroxypropyl glycols which are solid at ordinary temperatures but liquid at methylcellulose); fillers (including, but not limited to, lactose the rectal temperature and will therefore melt in the rectum and other Sugars, microcrystalline cellulose, pectin, gelatin, and release the drug. When formulated as a Suppository the calcium Sulfate, ethyl cellulose, polyacrylates or calcium compositions of the invention may be formulated with tradi hydrogen phosphate.); lubricants (including, but not limited tional binders and carriers, such as triglycerides. to, magnesium Stearate, talc, silica, Sollidal silicon dioxide, Stearic acid, metallic Stearates, hydrogenated vegetable oils, Topical Compositions corn starch, polyethylene glycols, sodium benzoate, Sodium acetate); disintegrants (including, but not limited to, starch, 0113. The term “topical refers to administration of an Sodium starch glycolate) and wetting agents (including, but inventive composition at, or immediately beneath, the point not limited to, sodium lauryl sulfate). Additional suitable of application. The phrase “topically applying describes carriers for the compositions of the present invention include, application onto one or more Surfaces(s) including epithelial but are not limited to, water, Salt Solutions, alcohol, vegetable Surfaces. Although topical administration, in contrast to oils, polyethylene glycols, gelatin, lactose, amylose, magne transdermal administration, generally provides a local rather sium Stearate, talc, silicic acid, Viscous paraffin, perfume oil; than a systemic effect, as used herein, unless otherwise stated fatty acid monoglycerides and diglycerides, petroethral fatty or implied, the terms topical administration and transdermal acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, administration are used interchangeably. For the purpose of and the like. The pharmaceutical preparations can be steril this application, topical applications shall include mouth ized and if desired, mixed with auxiliary agents, for example, washes and gargles. lubricants, preservatives, stabilizers, wetting agents, emulsi 0114 Topical administration may also involve the use of fiers, salts for influencing osmotic pressure, buffers, color transdermal administration Such as transdermal patches or ings, flavoring and/or aromatic Substances and the like which iontophoresis devices which are prepared according to tech do not deleteriously react with the active compounds. niques and procedures well known in the art. The terms 0118. The term “pharmaceutically acceptable carrier as “transdermal delivery system.” “transdermal patch' or used herein refers to any Substantially non-toxic carrier con “patch” refer to an adhesive system placed on the skin to ventionally useful for administration of pharmaceuticals in deliver a time released dose of a drug(s) by passage from the which the active component will remain stable and bioavail dosage form through the skin to be available for distribution able. In some embodiments, the pharmaceutically acceptable via the systemic circulation. Transdermal patches are a well carrier of the compositions of the present invention include a accepted technology used to deliver a wide variety of phar release agent Such as a Sustained release or delayed release maceuticals, including, but not limited to, Scopolamine for carrier. In Such embodiments, the carrier can be any material motion sickness, nitroglycerin for treatment of angina pecto capable of sustained or delayed release of the leptin peptide ris, clonidine for hypertension, estradiol for post-menopausal active ingredient to provide a more efficient administration, indications, and nicotine for Smoking cessation. resulting in less frequent and/or decreased dosage of the 0115 Patches suitable for use in the present invention active ingredient, ease of handling, and extended or delayed include, but are not limited to, (1) the matrix patch; (2) the effects. Non-limiting examples of Such carriers include lipo reservoir patch; (3) the multi-laminate drug-in-adhesive Somes, microSponges, microspheres, or microcapsules of patch; and (4) the monolithic drug-in-adhesive patch; Trans natural and synthetic polymers and the like. Liposomes may dermal and Topical Drug Delivery Systems, pp. 249-297 be formed from a variety of phospholipids such as choles (Tapash K. Ghosh et al. eds., 1997), hereby incorporated terol, Stearylamines or phosphatidylcholines. herein by reference. These patches are well known in the art 0119. In some embodiments, the compositions of the and generally available commercially. present invention can further include one or more compatible active ingredients aimed at providing the composition with Carriers and Other Components another pharmaceutical effect in addition to that provided by 0116. In some embodiments, the compositions of the a leptin composition, therapeutically active leptin, leptin present invention may be formulated with an excipient, mimic peptide or a derivative thereof. “Compatible' as used vehicle or carrier selected from solvents, Suspending agents, herein means that the active ingredients of such a composition binding agents, fillers, lubricants, disintegrants, and wetting are capable of being combined with each other in Such a agents/surfactants/solubilizing agents. The terms "excipi manner so that there is no interaction that would substantially ent', 'vehicle', or “carrier” refer to substances that facilitate reduce the efficacy of each active ingredient or the composi the use of, but do not deleteriously react with, the active tion under ordinary use conditions. In another aspect of the US 2009/029 1894 A1 Nov. 26, 2009

present invention, the composition also may be administered CAL BASIS OF THERAPEUTICS, Joel G. Harman, Lee E. serially or in combination with other compositions for treat Limbird, Eds.; McGraw Hill, New York, 2001: THE PHYSI ing diseases, conditions or disorders resulting from accumu CIAN'S DESK REFERENCE, Medical Economics Com lation of amyloid peptides. For example, without limitation, pany, Inc., Oradell, N.J., 1995; and DRUG FACTS AND Such other compositions may include monoclonal antibodies COMPARISONS, FACTS AND COMPARISONS, INC., St. (such as monoclonal anti-B-Amyloids and monoclonal anti Louis, Mo., 1993). The precise dose to be employed in the B-secretases); and anti-inflammatory compounds (including, formulation will also depend on the route of administration, but not limited to nonsteroidal anti-inflammatory drugs and the seriousness of the disease or disorder, and should be (NSAIDs), such as ibuprofen, indomethacin, and flurbipro decided according to the judgment of the practitioner and fen). Anti-inflammatory compounds have been shown to each patient's circumstances. Various administration patterns direct AB-lowering properties in cell cultures as well as in will be apparent to those skilled in the art. transgenic models of AD-like amyloidosis. 0.122 The dosage ranges for the administration of the 0120. The concentration of the active substance is selected compositions of the present invention are those large enough so as to exert its therapeutic effect, but low enough to avoid significant side effects within the scope and Sound judgment to produce the desired therapeutic effect. Preferably, the of the skilled artisan. The effective amount of the composition therapeutically effective amount of the compositions of the may vary with the age and physical condition of the biological present invention is administered one or more times per day subject being treated, the severity of the condition, the dura on a regular basis. A typical dose administered to a subject is tion of the treatment, the nature of concurrent therapy, the between about 0.01 mg of the composition per kg (of body specific compound, composition or other active ingredient weight) per day and about 0.5 mg of the composition per kg employed, the particular carrier utilized, and like factors. (of body weight) per day. For example, without limitation, the Those of skill in the art can readily evaluate such factors and, minimum dose of the composition is contemplated as about based on this information, determine the particular effective 0.01 mg/kg/day, about 0.025 mg/kg/day, about 0.05 mg/kg/ concentration of a composition of the present invention to be day, about 0.075 mg/kg/day, about 0.08 mg/kg/day, about 0.1 used for an intended purpose. Additionally, in therapeutic mg/kg/day, about 0.125 mg/kg/day, about 0.15 mg/kg/day, applications of the present invention, compositions or medi about 0.175 mg/kg/day, about 0.2 mg/kg/day, about 0.225 cants are administered to a patient Suspected of, having, or mg/kg/day, about 0.25 mg/kg/day, about 0.275 mg/kg/day, already Suffering from, Such a disease, disorder or condition about 0.3 mg/kg/day, about 0.325 mg/kg/day, about 0.35 in an amount Sufficient to cure, or at least partially arrest, the mg/kg/day, about 0.375 mg/kg/day, about 0.4 mg/kg/day, symptoms of the disease, disorder or condition, including its about 0.45 mg/kg/day, about 0.475 mg/kg/day, or about 0.5 complications and intermediate pathological phenotypes in mg/kg/day and the maximum dose is contemplated as about development of the disease, disorder or condition. In some 0.5 mg/kg/day, about 0.475 mg/kg/day, about 0.45 mg/kg/ methods, administration of the composition of the present day, about 0.4 mg/kg/day, about 0.375 mg/kg/day, about 0.35 invention reduces or eliminates cognitive impairment in mg/kg/day, about 0.325 mg/kg/day, about 0.3 mg/kg/day, patients that have not yet developed characteristic pathology about 0.275 mg/kg/day, about 0.25 mg/kg/day, bout 0.225 of the disease, disorder or condition. mg/kg/day, about 0.2 mg/kg/day, about 0.175 mg/kg/day, 0121 An amount adequate to accomplish therapeutic or about 0.15 mg/kg/day, about 0.125 mg/kg/day, about 0.1 prophylactic treatment is defined herein as a therapeutically mg/kg/day, about 0.08 mg/kg/day, about 0.075 mg/kg/day, effective dose. In both prophylactic and therapeutic regimes, about 0.05 mg/kg/day, about 0.025 mg/kg/day, or about 0.01 an amount of the compositions of the present invention is mg/kg/day. In some embodiments of the invention inhumans, usually administered in several dosages until a Sufficient ben the dose may be about 0.01 mg to about 0.3 mg of the com eficial response has been achieved. Typically, the response is position per kg (of body weight) per day, and in other embodi monitored and repeated dosages are given if the response ments in humans, between 0.01 and 0.08 mg of the compo starts to wane. A skilled artisan can determine a pharmaceu sition per kg (of body weight) per day. tically effective amount of the inventive compositions by I0123. Additional compositions of the present invention determining the dose in a dosage unit (meaning unit of use) can be prepared readily using technology is known in the art, that elicits a given intensity of effect, hereinafter referred to as such as that which is described in Remington's Pharmaceu the “unit dose.” The term "dose-intensity relationship’ refers tical Sciences, 18th or 19th editions, published by the Mack to the manner in which the intensity of effect in an individual Publishing Company of Easton, Pa., which is incorporated recipient relates to dose. The intensity of effect generally herein by reference. designated is 50% of maximum intensity. The corresponding dose is called the 50% effective dose or individual ED50. The Administration use of the term “individual distinguishes the ED50 based on the intensity of effect as used herein from the median effective 0.124. According to another embodiment of the method, dose, also abbreviated ED50, determined from frequency of the method comprises the step of implanting Surgically or response data in a population. “Efficacy” as used herein refers injecting a leptin composition gel, leptin composition slow to the property of the compositions of the present invention to release solid or leptin composition semisolid into the patient achieve the desired response, and “maximum efficacy” refers to deliver drug substance at the site of interest. Because the to the maximum achievable effect. The amount of compounds leptin composition gel, leptin composition slow-release solid in the compositions of the present invention which will be or leptin composition semisolid agent is delivered specifi effective in the treatment of a particular disorder or condition cally (locally) to the site, the dosage required to treat the will depend on the nature of the disorder or condition, and can progressive cognitive disorder will be appropriate, to reduce, be determined by standard clinical techniques. (See, for prevent or circumvent the main side effect that prevents the example, Goodman and Gilman's THE PHARMACOLOGI administration of higher systemic doses, e.g., toxicity. It is US 2009/029 1894 A1 Nov. 26, 2009

desired to deliver efficacious amounts of this agent to a spe prises a second therapeutic agent. According to another cific site (without unwanted side effects). embodiment, the second therapeutic agent is an antibiotic. According to another embodiment, the second therapeutic Controlled Release Systems agent is an anti-fungal agent. According to another embodi 0.125. The therapeutic agent(s), including, but not limited ment, the second therapeutic agent is an anti-viral agent. to, a leptin composition, may be contained in controlled According to another embodiment, the second therapeutic release systems. In order to prolong the effect of a drug, it agent is an anti-protozoal agent. According to another often is desirable to slow the absorption of the drug from embodiment, the second therapeutic agent is a steroidal anti Subcutaneous, intrathecal, or intramuscular injection. This inflammatory agent. According to another embodiment, the may be accomplished by the use of a liquid Suspension of second therapeutic agent is a non-steroidal anti-inflammatory crystalline or amorphous material with poor water solubility. agent. According to another embodiment, the second thera The rate of absorption of the drug then depends upon its rate peutic agent is an anti-oxidant. According to another embodi of dissolution which, in turn, may depend upon crystal size ment, the second therapeutic agent is a hormone. According and crystalline form. to another embodiment, the second therapeutic agent is a 0126 The term “controlled release' is intended to refer to Vitamin. According to another embodiment, the second thera any drug-containing formulation in which the manner and peutic agent is an antihistamine agent. According to another profile of drug release from the formulation are controlled. embodiment, the second therapeutic agent is a chemothera This refers to immediate as well as non-immediate release petic agent. formulations, with non-immediate release formulations 0.130 Those skilled in the art will recognize that initial including, but not limited to, Sustained release and delayed indications of the appropriate therapeutic dosage of the com release formulations. The term “sustained release' (also positions of the invention can be determined in in vitro and in referred to as “extended release') is used herein in its con Vivo animal model systems, and in human clinical trials. One ventional sense to refer to a drug formulation that provides for of skill in the art would know to use animal studies and human gradual release of a drug over an extended period of time, and experience to identify a dosage that can safely be adminis that preferably, although not necessarily, results in Substan tered without generating toxicity or other side effects. For tially constant blood levels of a drug over an extended time acute treatment, it is preferred that the therapeutic dosage be period. Alternatively, delayed absorption of a parenterally close to the maximum tolerated dose. For chronic preventive administered drug form is accomplished by dissolving or use, lower dosages may be desirable because of concerns suspending the drug in an oil vehicle. The term “delayed about long term effects. release' is used herein in its conventional sense to refer to a I0131 The effectiveness of the compositions and methods drug formulation in which there is a time delay between of the present invention can be assayed by a variety of proto administration of the formulation and the release of the drug cols. The effects of increasing cognitive function in a human there from. “Delayed release' may or may not involve subject can be determined by methods routine to those skilled gradual release of drug over an extended period of time, and in the art including, but not limited to, both paper and pencil, thus may or may not be “sustained release.” and computer tests. One of skill in the art can also directly 0127. Use of a long-term sustained release implant may be measure amyloid peptide accumulation levels, neurofibril particularly suitable for treatment of chronic conditions. The lary tangle formation and neurodegeneration in animal mod term “long-term' release, as used herein, means that the els. Furthermore, amyloid peptide may be measured in a implant is constructed and arranged to deliver therapeutic sample of a subject's cerebrospinal fluid (CSF) obtained by levels of the active ingredient for at least 7 days, and prefer spinal tap. One measure of accumulation of an amyloid pep ably about 30 to about 60 days. Long-term sustained release tide is an increase in levels circulating in the blood of a implants are well-known to those of ordinary skill in the art subject. Such levels may be measured by Sandwich Enzyme and include some of the release systems described above. linked-Immunoabsorbent-Assays (ELISAS), using a pair of 0128. According to another embodiment, the pharmaceu antibodies, one for capture and the other for detection. These tically acceptable carrier of the present invention includes a methods are well known by those of ordinary skill in the art. sustained release or delayed release carrier. The carrier can be (0132 Unless defined otherwise, all technical and scien any material capable of Sustained or delayed release of the tific terms used herein have the same meaning as commonly compound to provide a more efficient administration result understood by one of ordinary skill in the art to which this ing in less frequent and/or decreased dosage of the com invention belongs. Although any methods and materials simi pound, ease of handling, and extended or delayed effects on lar or equivalent to those described herein also can be used in epithelial-related conditions. the practice or testing of the present invention, the preferred 0129. According to another aspect, the described inven methods and materials are now described. All publications tion provides a method of improving resilience of cognitive mentioned herein are incorporated herein by reference to function in a subject in need thereof, the method comprising disclose and describe the methods and/or materials in con the step of (a) administering to the Subject a composition nection with which the publications are cited. comprising: (i) a cognitive function-enhancing amount of a 0.133 Where a range of values is provided, it is understood leptin composition, and (ii) a pharmaceutically acceptable that each intervening value, to the tenth of the unit of the lower carrier. According to one embodiment, the leptin composition limit unless the context clearly dictates otherwise, between comprises at least one of a leptin, a leptin mimic, a leptin the upper and lower limit of that range and any other stated or derivative, an AMP-dependent protein kinase activator, a lep intervening value in that stated range is encompassed within tin agonist, a leptin blocker, a mimic of a leptin blocker, a the invention. The upper and lower limits of these smaller leptin antagonist, an AMP-dependent protein kinase inhibi ranges which may independently be included in the Smaller tor; or pharmaceutically acceptable salts thereof. According ranges is also encompassed within the invention, Subject to to another embodiment, the leptin composition further com any specifically excluded limit in the stated range. Where the US 2009/029 1894 A1 Nov. 26, 2009

Stated range includes one or both of the limits, ranges exclud parts by weight, molecular weight is weight average molecu ing either both of those included limits are also included in the lar weight, temperature is in degrees Centigrade, and pressure invention. is at or near atmospheric. 0134) While the present invention has been described with reference to the specific embodiments thereof it should be Reagents and Antibodies understood by those skilled in the art that various changes I0140 Minimum essential medium (MEM) was purchased may be made and equivalents may be substituted without from ATCC (Manassas, Va.). Neurobasal medium, B27 departing from the true spirit and scope of the invention. In Supplement and L-glutamine were purchased from Gibco addition, many modifications may be made to adopt a par (Carlsbad, Calif.). Trypsin-EDTA and penicillin-streptomy ticular situation, material, composition of matter, process, cin-amphotercin solution were purchased from MP Biomedi process step or steps, to the objective spirit and scope of the cals (Solon, Ohio). Fetal bovine serum (FBS), all-trans ret present invention. All such modifications are intended to be inoic acid (RA), also known as ATRA, human recombinant within the scope of the claims appended hereto. Where a leptin and human recombinant insulin were purchased from range of values is provided, it is understood that each inter Sigma-Aldrich (St. Louis, Mo.). 5-Aminoimidazole-4-car vening value, to the tenth of the unit of the lower limit unless boxyamide ribonucleoside (AICAR), a drug widely used to the context clearly dictates otherwise, between the upper and activate AMP-dependent protein kinase (AMPK) experimen lower limit of that range and any other stated or intervening tally, was purchased from Cell Signaling Technology (Dan Value in that stated range is encompassed within the inven vers, Mass.). Upon activation, AMPK is known to promote tion. The upper and lower limits of these smaller ranges which lipolysis and to inhibit lipogenesis. may independently be included in the smaller ranges is also I0141 Rabbit anti-AMPKC. (pThr'7), Rabbit anti encompassed within the invention, subject to any specifically AMPKC. (total) and tau (pSer') mouse mAb were pur excluded limit in the stated range. Where the stated range chased from Cell Signaling Technology. Tau mouse mab includes one or both of the limits, ranges excluding either (clone 5E2) for detection of total tau was purchased from both of those included limits are also included in the inven Upstate Cell Signaling Solutions (Lake Placid, N.Y.). PHF t1On. tau mouse mAb (clone AT8) was purchased from Pierce Bio 0135. It must be noted that as used herein and in the technology (Rockford, Ill.). PHF-1 mouse mab was a gift appended claims, the singular forms “a”, “and”, and “the from Dr. Peter Davies, Albert Einstein College of Medicine include plural references unless the context clearly dictates (Bronx, N.Y.). Rabbit anti-leptin receptor (OB-R) and C-tu otherwise. All technical and scientific terms used herein have bulin mouse mAb were purchased from Affinity BioReagents the same meaning. (Golden, Colo.). Insulin receptor (B-subunit) mAb was pur I0136. The publications discussed herein are provided chased from Millipore (Billerica, Mass.). solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission Culture of Cell Lines that the present invention is not entitled to antedate such 0142. The human neuroblastoma, SH-SY5Y, and embryo publication by virtue of prior invention. Further, the dates of nal carcinoma, NTera-2 (NT2), cell lines were purchased publication provided may be different from the actual publi from AmericanType Culture Collection (ATCC). Cell culture cation dates which may need to be independently confirmed. was performed according to manufacturer's specific guide 0137 The present invention may be embodied in other lines. Briefly, SY5Y and NT2 cells were propagated on 25 specific forms without departing from the spirit or essential cm tissue-culture flasks (Corning; Corning, N.Y.) in mini attributes thereofand, accordingly, reference should be made mum essential medium (MEM) (Eagle) containing 10% fetal to the appended claims, rather than to the foregoing specifi bovine serum (FBS) until 80-90% confluence was estab cation, as indicating the scope of the invention. lished. SY5Y and NT2 cells were detached from the flask by 0138 While the present invention has been described with 0.1% trypsin-EDTA and gentle scraping, respectively, and reference to the specific embodiments thereof it should be sub-cultured at a ratio of 1:5. understood by those skilled in the art that various changes may be made and equivalents may be substituted without Neuronal Induction departing from the true spirit and scope of the invention. In 0143) To induce neuronal differentiation, 1x10 SY5Y or addition, many modifications may be made to adopt a par NT2 cells were seeded in 25 or 75 cm tissue-culture flasks, ticular situation, material, composition of matter, process, respectively. Cells were grown in neuronal induction medium process step or steps, to the objective spirit and scope of the (NIM), which consisted of MEM containing 5% FBS supple present invention. All such modifications are intended to be mented with 10 uMRA.SY5Y were grown in NIM for 6 days, within the scope of the claims appended hereto. and switched to serum-free NIM prior to treatment and har vesting on day 7. To induce neuronal differentiation of NT2 EXAMPLES cells was based on a previously described protocol P. W. Andrews, Retinoic acid induces neuronal differentiation of a I0139. The following examples are put forth so as to pro cloned human embryonal carcinoma cell line in vitro, Dev. vide those of ordinary skill in the art with a complete disclo Biol. 103 (1984) 285-293, which is incorporated herein by Sure and description of how to make and use the present reference. Briefly, NT2 cells were cultured in NIM for 5 invention, and are not intended to limit the scope of what the weeks, with 50% NIM replacement every 3 days. Differenti inventors regard as their invention nor are they intended to ated NT2 cells (NT2N) were switched to serum-free NIM on represent that the experiments below are all or the only the day prior to treatment and harvesting. experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, tem Culture of Rat Primary Neurons perature, etc.) but some experimental errors and deviations I0144) Primary rat cortical neurons were purchased from should be accounted for. Unless indicated otherwise, parts are Brain Bits LLC (Sprinfield, Ill.), and cultured as per manufac US 2009/029 1894 A1 Nov. 26, 2009

turer's instructions. Briefly, tissues were dispersed and Super 014.9 The first set of studies examined expression of the natant was transferred to a new tube and centrifuged for 1 min leptin receptor (OB-R) in RA-SY5Y cells treated with 400 at 1100 rpm. The neurons then were seeded in 6-well plates ng/ml leptin or placebo. Both treated and placebo cells were coated with poly-D-lysine (BDBiosciences; San Jose, Calif.) found to express relatively high levels of OB-R (FIG. 1A). We and grown in Neurobasal medium supplemented with B27 next determined whether leptin had an effect on tau phospho supplement (Invitrogen) and 0.5 mM L-glutamine. Medium rylation. Cells were treated for a range of time periods with was changed after 4 days, and at 7 days in culture the neurons 400 ng/ml leptin or placebo, and phosphorylation of tau at were treated and harvested. Ser', a site within the microtubule-binding region of tau, was measured (FIG. 1B and FIG. 1C). Significant (p<0.05) Protein Extraction and Western Blotting decreases in tau (Ser') phosphorylation were observed in cells treated with leptin for 1 hour, 2 hours or 4 hours com 0145 Western blot (or immunoblot) analysis is a method pared to placebo (FIG. 1C: far right bars). No change in tau to detect a specific protein in a given sample of a tissue (Ser) phosphorylation was observed in cells treated with homogenate or extract generally uses SDS-gel electrophore leptin for 24 hours compared to 4 hours (data not shown). sis to separate typically denatured proteins by the molecular 0150. To determine the dose-response relationship weight of the polypeptide. Proteins are then transferred to a between leptin and tau Ser' phosphorylation, RA-SY5Y membrane (typically nitrocellulose or PVDF) where they are cells were treated with leptin for 4 hours at a range of con detected using antibodies specific to the target protein. centrations (FIG. 1D and FIG.1E). We observed a significant 0146 Following treatment with leptin, insulin and/or (p<0.05) decrease in tau (Ser') phosphorylation in cells AICAR, SY5Y, NT2N and rat cortical neurons were har treated with 100 ng/ml leptin (FIG. 1E; second bar from left). vested by scraping. Cell pellets were washed twice in ice-cold Decreasing tau (Ser') phosphorylation was observed up to 1xPBS (phosphate buffered saline) (pH 7.4), resuspended in a concentration of 1600 ng/ml leptin (second bar from right), protease and phosphotase inhibitor-supplemented 1xRIPA which produced the maximal effect. Estimation of the 50% lysis/extraction buffer consisting of 25 mM Tris-HCl, pH 7.6, inhibitory concentration (ICs) of leptin for tau (Ser') phos 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate and phorylation provided a value of 750 ng/ml, or 46.9 nM. 0.1% SDS (Pierce), and then subjected to freeze/thaw cycles in a dry ice/ethanol bath. Cell-free, whole cell lysates were Example 2 obtained and total protein was determined with the Coo massie (Bradford) Protein Assay Kit (Pierce). Whole cell Insulin and Tau Phosphorylation in RA-Induced extracts (25 ug) were analyzed by western blots using 10% SY5Y Cells SDS-PAGE pre-cast gels (Lonza; Rockland, Me.), and the 0151. We tested the effect of insulin treatment on tau separated proteins were transferred onto polyvinylidene dif (Ser) phosphorylation in RA-SY5Y cells and compared it luoride membranes (Millipore). Membranes were incubated to that of leptin. overnight at 4°C. with primary antibodies and then detected 0152 The first set of studies examined expression of the the following day by 2 hr incubation with HRP-conjugated insulin receptor in RA-SY5Y cells treated with 10 uM insulin IgG. All primary antibodies, except tau-pSer' (1:500), total or placebo. Both insulin and placebo-treated cells were found tau (1:500) and PHF-tau AT8 (1:200), and secondary antibod to express high levels of insulin receptor (FIG. 2A). We next ies were used at final dilutions of 1:1,000 and 1:10,000, determined the effect of insulin on tau phosphorylation. Cells respectively. HRP was developed with SuperSignal West Pico were treated for a range of time periods with 10 uM insulin or Chemiluminescent Substrate (Pierce), and imaged using a placebo, and phosphorylation of tau (Ser') was measured BioRad (Hercules, Calif.) ChemiDoc XRS System. The (FIG. 2B and FIG. 2C). Significant (p<0.05) decreases in tau membranes were stripped with Restore PLUS Western Blot (Ser) phosphorylation were observed in cells treated with Stripping Buffer (Pierce) for reprobing with other antibodies. insulin for 2 hours or 4 hours compared to placebo-treated Blocking buffer consisted of 5% milk in 0.1% Tween in TBS cells (FIG. 2C; far right bars). No change in tau (Ser') (Tris buffered saline). phosphorylation was observed in cells treated with insulin for 24 hours compared to 4 hours (data not shown). Statistical Analysis 0153. As in the leptin studies (FIG. 1D and FIG. 1E), a dose-response curve for insulin on tau (Ser') phosphoryla 0147 Statistical data analyses were performed with analy tion was established in RA-SY5Y cells (FIG. 2D and FIG. sis of variance and Tukey-Kramer multiple comparisons test. 2E). We observed a significant (p<0.05) decrease in tau Densitometric analyses were performed using the (Ser) phosphorylation in cells treated with 10 uM insulin UN-SCAN-IT gel 6.1 software (Silk Scientific: Orem, Utah). (FIG.2E.; third bar from right). Further, maximum decrease of p<0.05 was considered statistically significant. tau (Ser') phosphorylation was observed at a concentration of 20 uM insulin (second bar from right). Estimation of the Example 1 50% inhibitory concentration (ICs) of insulin for tau (Ser') Leptin and Tau Phosphorylation in RA-Induced phosphorylation provided a value of 13.8 LM. SYSY Cells SUMMARY 0148 RA induction of the human neuroblastoma cell line, 0154 The effect of leptin on the level of tau phosphoryla SY5Y. has been reported to induce hyperphosphorylation of tion at sites known to be hyperphosphorylated in AD was tau at AD-related sites. We therefore utilized SY5Y cells studied. RA-induced, human SY5Y express hyperphospho induced with retinoic acid (RA-SY5Y) for 7 days as our rylated tau, and thus were utilized in our treatment model. primary in vitro model to investigate the effects of leptin and Since insulin reduces the level of phosphorylated tau in both other treatments on tau phosphorylation. in vitro and in Vivo models, our studies began by comparing US 2009/029 1894 A1 Nov. 26, 2009 the efficacy of leptin to insulin (FIGS. 1 and 2). Leptin was a significant (p<0.05) increase in tau phosphorylation com found to reduce tau phosphorylation by 50% at a concentra pared to co-treatment alone (FIG. 3D: first and second bars tion (FIG. 1; ICs, 46.9 nM) that was 300-fold less than that from left). Cells post-treated with cold PBS for 1 hour showed of insulin (FIG. 2: ICs-13.8 uM). significant (p<0.01) hyperphosphorylation of tau compared to cells with no treatment at all (first bar from right). These Example 3 results suggest that the effects of leptin and insulin on dephos Combined Leptin and Insulin Treatment and Tau phorylation of tau are reversible. The results also demonstrate Phosphorylation antibody specificity regarding the phosphorylated form of tall. O155 RA-SY5Y cells were treated for 4 hours with sub optimal or maximum effect doses, either in combination or alone, of leptin and/or insulin, and tau (Ser') phosphoryla Example 5.1 tion was measured (FIG. 3A and FIG. 3B). A significant Leptin, Insulin and Tau Phosphorylation at Other (p<0.05) decrease in phosphorylation was observed in cells AD-Related Sites treated with sub-optimal combinations of leptin (100 ng/ml) and insulin (1 uM) compared to either treatment alone (FIG. 0158 To evaluate if the observed effects of leptin and 3B: first, third and fifth bars from left). Co-treatment with insulin on tauphosphorylation at Ser' (FIG. 1 and FIG.2) is maximum effect doses of leptin (1600 ng/ml) and insulin (20 consistent with other AD-related sites, antibodies raised uM) produced the most significant (p<0.01) decrease in phos against tau epitopes known to be phosphorylated in paired phorylation (first bar from right) compared to placebo helical filament (PHF) tau were utilized. PHFs are a principal treated. Co-treatment with maximum effect doses of leptin component of NFT pathology, which results from tau hyper and insulin did not produce a significant (pa0.05) reduction in phosphorylation and Subsequent microtubule destabilization tau (Ser') phosphorylation compared to either treatment and oligomerformation. Tauphosphorylated at Ser' and alone. Ser'/Thr' is recognized by PHF-1 (mouse) and AT8 (mouse) antibodies, respectively. SUMMARY 0159 RA-SY5Y cells were treated with leptin and/or 0156 The combined treatment with sub-optimal doses of insulin as in FIG. 3A and FIG. 3B, and phosphorylation of leptin (100 ng/ml) and insulin (1 LM) produced a significant specific tau sites was measured (Table 1).

TABLE 1 Relative tau phosphorylation in treated neuronal cultures

Treatment Leptin Leptin 100 ng/ml + 1600 ng/ml + Cell Non- Leptin Leptin Leptin Insulin Insulin Insulin Insulin Type PhosphoSite Treated 100 ng/ml 800 ng/ml 1600 ng/ml 1 M 20 M 1 M 20 M RA- pSer396 0 -26 - 6* ND -51 S* -23 4* -47 14* -5810 - 69 12* SYSY PHF-1 O -2019 ND -674 -37 - 11* -807* -723* -84 + 6* AT8 O -105 ND -60 19* -40 13* -57 - 14* -61 - 17 -66 - 21* NT2N pSer96 O -27 6* ND -27 S* -23 6* -53 10* -427* -481* Rat1 PHF-1 O ND -75 - 18 ND ND ND ND ND Neuron AT8 O ND S 23 ND ND ND ND ND decrease in tauphosphorylation compared to either treatment (0160 Briefly, RA-induced SY5Y and NT2N were treated alone (FIG.3). This result demonstrates the potential benefits with low and high concentrations of leptin (100 ng/ml or 1600 of a combinatorial treatment for AD, as leptin and insulin may ng/ml) and/or insulin (1 M or 20 uM) for 4 hours, or non produce an additive effect. treated (placebo). Primary rat cortical neurons were treated with leptin for 24 hours or placebo. Whole cell extracts were Example 4 prepared and analyzed by Western blot with phosphorylated Reversibility of Leptin- and Insulin-Induced Dephos tau-specific antibodies (pSer', PHF-1 or AT8). Membranes phorylation were stripped and re-probed with anti-tau (total) for normal ization. Normalized band densities were analyzed by densi 0157 Tau phosphorylation has been reported to increase tometry and results are presented as the meantSD percent with cold temperature stress in animals. We thus utilized a fold change, relative to non-treated Samples, which were arbi similar approach to determine whether the leptin- and insulin trarily assigned a value of 0. (ND Not Determined). (p<0. induced dephosphorylation of tau at Ser' was reversible. 05 vs non-treated). RA-SY5Y were co-treated with leptin (1600 ng/ml) and insu 0.161 Leptin and/or insulin treatment was observed to lin (20M) for 4 hours, or placebo. At the end of the treatment have a similar effect on the phosphorylation of tau as detected period, cells were either harvested or post-treated with ice by PHF-1 and AT8 antibodies (Table 1). The only observable cold PBS (pH 7.4) for 10 minutes or 1 hour (FIG.3C and FIG. difference was that leptin at 100 ng/ml was unable to induce 3D). Cells post-treated with cold PBS for 10 minutes showed a significant (pa0.05) decrease in phosphorylation of tau, US 2009/029 1894 A1 Nov. 26, 2009 20 compared to that observed with pSer'antibody. These find (0169 RA-SY5Y were treated with AICAR for 1 hour at a ings demonstrate that both leptin and insulin treatment of range of concentrations, to establisha dose-response relation RA-SY5Y cells reduces phosphorylation of at least two sepa ship (FIG. 4D and FIG. 4E). We observed a significant (p<0. rate AD-related tau sites. 05) decrease in Serphosphorylation in cells treated with 1 mM AICAR (FIG. 4E; third bar from right). Decreasing Example 5.2 Serphosphorylation was observed up to a concentration of Leptin, Insulin and Tau Phosphorylation in Other 2 mMAICAR (second bar from right), which produced the maximal effect. Estimation of the 50% inhibitory concentra Neuronal Cells tion (ICs) of AICAR for tau (Ser) phosphorylation pro (0162 We next determined whether the effect of leptin vided a value of 2.7 mM. and/or insulin on tau phosphorylation was unique to 0170 In summary, the observed results suggest that acti RA-SY5Y cells or consistent with other neuronal cells. For vation of AMPKC, by either leptin or insulin, could produce this approach, we utilized human NT2 cells, which undergo similar effects on tau phosphorylation at AD-related sites. neuronal differentiation with R', 'reatment (NT2N), as well as 0171 The point of convergence of the post-receptor sig rat primary cortical neurons. naling pathways in tau phosphorylation, was investigated. (0163 NT2N cells were treated with leptin and/or insulin The energy homeostasis enzyme AMPK (FIG. 4) is known to as in FIG.3A and FIG.3B, and tau phosphorylation at Ser' be activated by insulin and leptin and is also known to interact was measured (Table 1). Insulin and combined insulin/leptin with glycogen synthase kinase-3? (GSK-3?). Activation of treatment were observed to have a similar effect to that AMPK with AICAR produced significant changes in tau observed with RA-SY5Y cells (Table 1). phosphorylation within 10 minutes. These findings Suggest 0164. For the rat primary neurons, we determined the that AMPK may provide a novel therapeutic target for reduc effect of 24 hour leptin treatment on phosphorylation of tau, ing AD-related tau phosphorylation. We demonstrated that as detected by PHF-1 and AT8 antibodies (Table 1). A mid activation of AMPK mimics the leptin/insulin effect. range dose of leptin (800 ng/ml) was chosen, since this con centration produced a 50% decrease (IDs) in tau phospho Example 7 rylation within RA-SY5Y (FIG. 1). Leptin produced a significant (p<0.05) decrease in tau phosphorylation, as Clinical Trials detected by PHF-1 antibody compared to placebo-treated 0172. The clinical development of leptin in humans is cells (Table 1). However, the leptin-induced decrease in tau investigated. A pilot trial, placebo-cotrolled double blinded phosphorylation was not detected by the AT8 antibody (Table involving three groups of equal number of patients, diagnosed 1). with early-stage Alzheimer's disease, receive by Subcutane 0.165. In summary, leptin induces a reduction in phospho ous injections 0 mg (placebo), 5 mg, or 10 mg of leptin once rylation of tau at Ser' (as detected by PHF-1 antibody) daily for 16 weeks. CSF and serum samples are obtained in in several neuronal cells. Further, it induces a reduction of tau the beginning, during and at the end of the trial and Ab40, phosphorylation at Ser'/Thr' (as detected by AT8 anti Ab42 and phosphor-tau are measured. Patients also receive body) in most but not all neuronal cell types tested. neuropsychological evaluations at the beginning and at the end of the trial. This trial validates the preclinical findings and SUMMARY demonstrates leptin's value in selectively targeting both 0166 Tau phosphorylation in human NT2N cells and rat pathologies of AD. primary cortical neurons (Table 1) was examined to demon 0173 The clinical trial data, taken with the preclinical data strate the effects of leptin were consistent with other neuronal demonstrates that leptin ameliorates both A? and tau-related systems. Similar results were observed as in RA-SY5Y pathologies. Together with leptin's pharmacological profile except that leptin did not significantly change phosphoryla these data Support its use as a novel therapeutic for Alzhe tion of Ser'/Thr' (AT8 mouse mab) in rat cortical neu imer's disease. rons. Without being limited by theory, this result may be related to the antibodies species specificity. Example 8 RA-Induced SY5Y and NT2N Treated with Leptin Example 6 or Insulin AMPK Signaling and Tau Phosphorylation in 0.174 RA-induced SY5Y and NT2N were treated with RA-SYSY Cells low or high concentrations of leptin (100 ng/ml or 1600 0167. The energy homeostasis enzyme AMP-activated ng/ml, respectively) and/or insulin (1 M or 20 M, respec protein kinase (AMPK) was directly stimulated with the cell tively) for 4 hours, or non-treated (placebo) (Table 1). Pri permeable activator, AICAR to study the influence of leptin mary rat cortical neurons were treated with leptin for 24 hours and insulin in modulating tau phosphorylation. or placebo. Whole cell extracts were prepared and analyzed 0168 AICAR treatment produced a large increase in by western blot with phosphorylated tau-specific antibodies pThr' AMPKC. band density (FIG. 4A, top row), thus dem (pSer”, PHF-1 or AT8). Membranes were stripped and re onstrating efficient activation of AMPKC. We next deter probed with anti-tau (total) for normalization. Normalized mined the effect of AICAR on tau phosphorylation. band densities were analyzed by densitometry and results are RA-SY5Y were treated for various amounts of time with 1 presented as the meantSD percent fold change, relative to mMAICAR or placebo-treated (FIG. 4B and FIG. 4C). Sig non-treated Samples, which were arbitrarily assigned a value nificant (p<0.05) decreases in Ser' phosphorylation were of 0. (ND Not Determined). *p-0.05 vs. non-treated. observed in cells treated with AICAR from 10 minutes to 4 (0175 While the present invention has been described with hours, compared to placebo (FIG. 4C., gray bars). reference to the specific embodiments thereof it should be US 2009/029 1894 A1 Nov. 26, 2009 21 understood by those skilled in the art that various changes ticular situation, material, composition of matter, process, may be made and equivalents may be substituted without process step or steps, to the objective spirit and scope of the departing from the true spirit and scope of the invention. In present invention. All such modifications are intended to be addition, many modifications may be made to adopt a par- within the scope of the claims appended hereto.

SEQUENCE LISTING

<16 Oc NUMBER OF SEO ID NOS: 6

<210 SEQ ID NO 1 &2 11s LENGTH: 770 &212> TYPE: PRT <213> ORGANISM: Homo sapiens <4 OO SEQUENCE: 1 Met Lieu Pro Gly Lieu Ala Lieu Lleu Lleu Lieu Ala Ala Trp Thr Ala Arg 1. 5 1O 15 Ala Lieu. Glu Val Pro Thir Asp Gly Asn Ala Gly Lieu. Lieu Ala Glu Pro 2O 25 3 O Glin Ile Ala Met Phe Cys Gly Arg Lieu. Asn Met His Met Asn Val Glin 35 4 O 45 Asn Gly Llys Trp Asp Ser Asp Pro Ser Gly. Thir Lys Thir Cys Ile Asp SO 55 60 Thr Lys Glu Gly Ile Leu Gln Tyr Cys Glin Glu Val Tyr Pro Glu Lieu. 65 70 7s 8O

Glin Ile Thir Asn. Wal Wall Glu Ala Asn. Glin Pro Wall Thr le Glin Asn 85 90 95 Trp Cys Lys Arg Gly Arg Lys Gln Cys Llys Thr His Pro His Phe Val 1OO 105 110 Ile Pro Tyr Arg Cys Lieu Val Gly Glu Phe Val Ser Asp Ala Lieu. Lieu. 115 12O 125 Val Pro Asp Llys Cys Llys Phe Lieu. His Glin Glu Arg Met Asp Val Cys 13 O 135 14 O Glu Thir His Lieu. His Trp His Thr Val Ala Lys Glu Thr Cys Ser Glu 145 15 O 155 16 O Llys Ser Thr Asn Lieu. His Asp Tyr Gly Met Lieu. Lieu Pro Cys Gly Ile 1.65 17 O 17s Asp Llys Phe Arg Gly Val Glu Phe Val Cys Cys Pro Lieu Ala Glu Glu 18O 185 190 Ser Asp Asn Val Asp Ser Ala Asp Ala Glu Glu Asp Asp Ser Asp Val 195 2 OO 2O5 Trp Trp Gly Gly Ala Asp Thr Asp Tyr Ala Asp Gly Ser Glu Asp Llys 210 215 22 O

Wal Wall Glu Wall Ala Glu Glu Glu Glu Wall Ala Glu Wall Glu Glu Glu 225 23 O 235 24 O Glu Ala Asp Asp Asp Glu Asp Asp Glu Asp Gly Asp Glu Val Glu Glu 245 25 O 255 Glu Ala Glu Glu Pro Tyr Glu Glu Ala Thr Glu Arg Thr Thr Ser Ile 26 O 265 27 O Ala Thr Thr Thr Thr Thr Thr Thr Glu Ser Val Glu Glu Val Val Arg 27s 28O 285

Glu Val Cys Ser Glu Glin Ala Glu Thr Gly Pro Cys Arg Ala Met Ile 290 295 3OO

Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Lys Cys Ala Pro Phe Phe US 2009/029 1894 A1 Nov. 26, 2009 22

- Continued

3. OS 310 315 32O Tyr Gly Gly Cys Gly Gly Asn Arg Asn. Asn. Phe Asp Thr Glu Glu Tyr 3.25 330 335 Cys Met Ala Val Cys Gly Ser Ala Met Ser Glin Ser Lieu. Leu Lys Thr 34 O 345 35. O Thr Glin Glu Pro Leu Ala Arg Asp Pro Val Lys Lieu Pro Thr Thr Ala 355 360 365 Ala Ser Thr Pro Asp Ala Val Asp Llys Tyr Lieu. Glu Thr Pro Gly Asp 37 O 375 38O Glu Asn. Glu. His Ala His Phe Glin Lys Ala Lys Glu Arg Lieu. Glu Ala 385 390 395 4 OO Llys His Arg Glu Arg Met Ser Glin Val Met Arg Glu Trp Glu Glu Ala 4 OS 41O 415 Glu Arg Glin Ala Lys Asn Lieu Pro Lys Ala Asp Llys Lys Ala Val Ile 42O 425 43 O Glin His Phe Glin Glu Lys Val Glu Ser Lieu. Glu Glin Glu Ala Ala Asn 435 44 O 445 Glu Arg Glin Glin Lieu Val Glu Thir His Met Ala Arg Val Glu Ala Met 450 45.5 460 Lieu. Asn Asp Arg Arg Arg Lieu Ala Lieu. Glu Asn Tyr Ile Thir Ala Lieu. 465 470 47s 48O Gln Ala Val Pro Pro Arg Pro Arg His Val Phe ASn Met Lieu Lys Lys 485 490 495 Tyr Val Arg Ala Glu Gln Lys Asp Arg Gln His Thr Lieu Lys His Phe SOO 505 51O Glu. His Val Arg Met Val Asp Pro Llys Lys Ala Ala Glin Ile Arg Ser 515 52O 525 Glin Val Met Thr His Lieu. Arg Val Ile Tyr Glu Arg Met Asn Glin Ser 53 O 535 54 O Lieu. Ser Lieu. Lieu. Tyr Asn Val Pro Ala Val Ala Glu Glu Ile Glin Asp 5.45 550 555 560 Glu Val Asp Glu Lieu. Lieu Gln Lys Glu Glin Asn Tyr Ser Asp Asp Wall 565 st O sts Lieu Ala Asn Met Ile Ser Glu Pro Arg Ile Ser Tyr Gly Asn Asp Ala 58O 585 59 O Lieu Met Pro Ser Lieu. Thr Glu Thir Lys Thr Thr Val Glu Lieu. Leu Pro 595 6OO 605 Val Asn Gly Glu Phe Ser Lieu. Asp Asp Lieu. Glin Pro Trp His Ser Phe 610 615 62O Gly Ala Asp Ser Val Pro Ala Asn Thr Glu Asn. Glu Val Glu Pro Val 625 630 635 64 O Asp Ala Arg Pro Ala Ala Asp Arg Gly Lieu. Thir Thr Arg Pro Gly Ser 645 650 655 Gly Lieu. Thir Asn. Ile Llys Thr Glu Glu Ile Ser Glu Val Lys Met Asp 660 665 67 O Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Glin Llys Lieu 675 68O 685 Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly 69 O. 695 7 OO Lieu Met Val Gly Gly Val Val Ile Ala Thr Val Ile Val Ile Thr Lieu. 7 Os 71O 71s 72O US 2009/029 1894 A1 Nov. 26, 2009 23

- Continued

Val Met Leu Lys Llys Lys Glin Tyr Thr Ser Ile His His Gly Val Val 72 73 O 73 Glu Val Asp Ala Ala Val Thr Pro Glu Glu Arg His Lieu. Ser Lys Met 740 74. 7 O Gln Glin Asn Gly Tyr Glu Asn Pro Thr Tyr Llys Phe Phe Glu Gln Met 7ss 760 765

Glin Asn 770

<210 SEQ ID NO 2 <211 LENGTH: 751. &212> TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OO SEQUENCE: 2 Met Lieu Pro Gly Lieu Ala Lieu. Lieu. Lieu. Lieu Ala Ala Trp Thir Ala Arg 1. 5 1O 15 Ala Lieu. Glu Val Pro Thr Asp Gly Asn Ala Gly Lieu. Lieu Ala Glu Pro 2O 25 3O Glin Ile Ala Met Phe Cys Gly Arg Lieu. Asn Met His Met Asn Val Glin 35 4 O 45 Asn Gly Lys Trp Asp Ser Asp Pro Ser Gly Thr Llys Thr Cys Ile Asp SO 55 6 O Thr Lys Glu Gly Ile Leu Gln Tyr Cys Glin Glu Val Tyr Pro Glu Lieu. 65 70 7s 8O

Glin Ile Thir Asn. Wal Wall Glu Ala Asn. Glin Pro Wall. Thir Ile Glin Asn 85 90 95 Trp. Cys Lys Arg Gly Arg Lys Glin Cys Llys Thr His Pro His Phe Val 1OO 105 11 O Ile Pro Tyr Arg Cys Lieu Val Gly Glu Phe Val Ser Asp Ala Lieu. Lieu. 115 12 O 125 Val Pro Asp Llys Cys Llys Phe Lieu. His Glin Glu Arg Met Asp Val Cys 13 O 135 14 O Glu Thr His Lieu. His Trp His Thr Val Ala Lys Glu Thr Cys Ser Glu 145 150 155 160 Llys Ser Thr Asn Lieu. His Asp Tyr Gly Met Lieu Lleu Pro Cys Gly Ile 1.65 17O 17s Asp Llys Phe Arg Gly Val Glu Phe Val Cys Cys Pro Lieu Ala Glu Glu 18O 185 19 O Ser Asp Asn. Wall Asp Ser Ala Asp Ala Glu Glu Asp Asp Ser Asp Wall 195 2OO 2O5 Trp Trp Gly Gly Ala Asp Thr Asp Tyr Ala Asp Gly Ser Glu Asp Llys 21 O 215 22O

Wal Wall Glu Wall Ala Glu Glu Glu Glu Wall Ala Glu Wall Glu Glu Glu 225 23 O 235 24 O Glu Ala Asp Asp Asp Glu Asp Asp Glu Asp Gly Asp Glu Val Glu Glu 245 250 255 Glu Ala Glu Glu Pro Tyr Glu Glu Ala Thr Glu Arg Thr Thr Ser Ile 26 O 265 27 O Ala Thr Thir Thr Thr Thr Thr Thr Glu Ser Val Glu Glu Val Val Arg 27s 28O 285 Glu Val Cys Ser Glu Glin Ala Glu Thr Gly Pro Cys Arg Ala Met Ile US 2009/029 1894 A1 Nov. 26, 2009 24

- Continued

29 O 295 3 OO Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Lys Cys Ala Pro Phe Phe 3. OS 310 315 32O Tyr Gly Gly Cys Gly Gly Asn Arg Asn. Asn. Phe Asp Thr Glu Glu Tyr 3.25 330 335 Cys Met Ala Val Cys Gly Ser Ala Ile Pro Thr Thr Ala Ala Ser Thr 34 O 345 35. O Pro Asp Ala Val Asp Llys Tyr Lieu. Glu Thr Pro Gly Asp Glu Asn. Glu 355 360 365 His Ala His Phe Glin Lys Ala Lys Glu Arg Lieu. Glu Ala Lys His Arg 37 O 375 38O Glu Arg Met Ser Glin Val Met Arg Glu Trp Glu Glu Ala Glu Arg Glin 385 390 395 4 OO Ala Lys Asn Lieu Pro Lys Ala Asp Llys Lys Ala Val Ile Glin His Phe 4 OS 41O 415 Glin Glu Lys Val Glu Ser Lieu. Glu Glin Glu Ala Ala Asn. Glu Arg Glin 42O 425 43 O Glin Lieu Val Glu Thir His Met Ala Arg Val Glu Ala Met Lieu. Asn Asp 435 44 O 445 Arg Arg Arg Lieu Ala Lieu. Glu Asn Tyr Ile Thr Ala Lieu. Glin Ala Val 450 45.5 460 Pro Pro Arg Pro Arg His Val Phe ASn Met Lieu Lys Llys Tyr Val Arg 465 470 47s 48O Ala Glu Gln Lys Asp Arg Glin His Thir Lieu Lys His Phe Glu. His Val 485 490 495 Arg Met Val Asp Pro Llys Lys Ala Ala Glin Ile Arg Ser Glin Val Met SOO 505 51O Thir His Lieu. Arg Val Ile Tyr Glu Arg Met Asn. Glin Ser Lieu. Ser Lieu. 515 52O 525 Lieu. Tyr Asn Val Pro Ala Val Ala Glu Glu Ile Glin Asp Glu Val Asp 53 O 535 54 O Glu Lieu. Lieu. Glin Lys Glu Glin Asn Tyr Ser Asp Asp Val Lieu Ala Asn 5.45 550 555 560 Met Ile Ser Glu Pro Arg Ile Ser Tyr Gly Asn Asp Ala Leu Met Pro 565 st O sts Ser Lieu. Thr Glu Thir Lys Thr Thr Val Glu Lieu Lleu Pro Val Asn Gly 58O 585 59 O Glu Phe Ser Lieu. Asp Asp Lieu. Glin Pro Trp His Ser Phe Gly Ala Asp 595 6OO 605 Ser Val Pro Ala Asn Thr Glu Asn. Glu Val Glu Pro Val Asp Ala Arg 610 615 62O Pro Ala Ala Asp Arg Gly Lieu. Thir Thr Arg Pro Gly Ser Gly Lieu. Thir 625 630 635 64 O Asn. Ile Llys Thr Glu Glu Ile Ser Glu Val Lys Met Asp Ala Glu Phe 645 650 655 Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Lieu Val Phe Phe 660 665 67 O Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Lieu Met Val 675 68O 685 Gly Gly Val Val Ile Ala Thr Val Ile Val Ile Thr Lieu Val Met Leu 69 O. 695 7 OO US 2009/029 1894 A1 Nov. 26, 2009 25

- Continued

Llys Llys Lys Glin Tyr Thir Ser Ile His His Gly Val Val Glu Val Asp 7 Os 71O 72O

Ala Ala Wall Thr Pro Glu Glu Arg His Luell Ser Llys Met Glin Glin Asn 72 73 O 73

Gly Tyr Glu Asn Pro Thir Tyr Lys Phe Phe Glu Gln Met Glin Asn 740 74. 7 O

<210 SEQ ID NO 3 <211 LENGTH: 695 &212> TYPE : PRT <213> ORGANISM: Homo sapiens

<4 OO SEQUENCE: 3

Met Leu Pro Gly Lell Ala Lell Luell Luell Luell Ala Ala Trp Thir Ala Arg 1. 5 15

Ala Luell Glu Wall Pro Thir Asp Gly Asn Ala Gly Lell Lell Ala Glu Pro 25 3O

Glin Ile Ala Met Phe Gly Arg Luell Asn Met His Met Asn Wall Glin 35 4 O 45

Asn Gly Trp Asp Ser Asp Pro Ser Gly Thir Lys Thir Ile Asp SO 55 6 O

Thir Glu Gly Ile Lell Glin Glin Glu Wall Pro Glu Luell 65 70

Glin Ile Thir Asn Wall Wall Glu Ala Asn Glin Pro Wall Thir Ile Glin Asn 85 90 95

Trp Arg Gly Arg Glin Cys Thir His Pro His Phe Wall 105 11 O

Ile Pro Tyr Arg Lell Wall Gly Glu Phe Wall Ser Asp Ala Luell Luell 115 12 O 125

Wall Pro Asp Cys Phe Luell His Glin Glu Arg Met Asp Wall 13 O 135 14 O

Glu Thir His Luell His Trp His Thir Wall Ala Lys Glu Thir Ser Glu 145 150 155 160

Ser Thir Asn Lell His Asp Gly Met Luell Lell Pro Gly Ile 1.65 17s

Asp Phe Arg Gly Wall Glu Phe Wall Pro Lell Ala Glu Glu 18O 185 19 O

Ser Asp Asn Wall Asp Ser Ala Asp Ala Glu Glu Asp Asp Ser Asp Wall 195

Trp Trp Gly Gly Ala Asp Thir Asp Ala Asp Gly Ser Glu Asp 21 O 215 22O

Wall Wall Glu Wall Ala Glu Glu Glu Glu Wall Ala Glu Wall Glu Glu Glu 225 23 O 235 24 O

Glu Ala Asp Asp Asp Glu Asp Asp Glu Asp Gly Asp Glu Wall Glu Glu 245 250 255

Glu Ala Glu Glu Pro Glu Glu Ala Thir Glu Arg Thir Thir Ser Ile 26 O 265 27 O

Ala Thir Thir Thir Thir Thir Thir Thir Glu Ser Wall Glu Glu Wall Wall Arg 27s 285

Wall Pro Thir Thir Ala Ala Ser Thir Pro Asp Ala Wall Asp Luell 29 O 295 3 OO

Glu Thir Pro Gly Asp Glu Asn Glu His Ala His Phe Glin Ala US 2009/029 1894 A1 Nov. 26, 2009 26

- Continued

3. OS 310 315 32O Glu Arg Lieu. Glu Ala Lys His Arg Glu Arg Met Ser Glin Val Met Arg 3.25 330 335 Glu Trp Glu Glu Ala Glu Arg Glin Ala Lys Asn Lieu Pro Lys Ala Asp 34 O 345 35. O Llys Lys Ala Val Ile Glin His Phe Glin Glu Lys Val Glu Ser Lieu. Glu 355 360 365 Glin Glu Ala Ala Asn. Glu Arg Glin Glin Lieu Val Glu Thir His Met Ala 37 O 375 38O Arg Val Glu Ala Met Lieu. Asn Asp Arg Arg Arg Lieu Ala Lieu. Glu Asn 385 390 395 4 OO Tyr Ile Thr Ala Lieu. Glin Ala Val Pro Pro Arg Pro Arg His Val Phe 4 OS 41O 415 Asn Met Lieu Lys Llys Tyr Val Arg Ala Glu Gln Lys Asp Arg Gln His 42O 425 43 O Thir Lieu Lys His Phe Glu. His Val Arg Met Val Asp Pro Llys Lys Ala 435 44 O 445 Ala Glin Ile Arg Ser Glin Val Met Thr His Leu Arg Val Ile Tyr Glu 450 45.5 460 Arg Met Asin Glin Ser Lieu. Ser Lieu. Lieu. Tyr Asn Val Pro Ala Val Ala 465 470 47s 48O Glu Glu. Ile Glin Asp Glu Val Asp Glu Lieu. Lieu Gln Lys Glu Glin Asn 485 490 495 Tyr Ser Asp Asp Val Lieu Ala Asn Met Ile Ser Glu Pro Arg Ile Ser SOO 505 51O Tyr Gly Asn Asp Ala Leu Met Pro Ser Lieu. Thr Glu Thir Lys Thir Thr 515 52O 525 Val Glu Lieu. Lieu Pro Val Asn Gly Glu Phe Ser Lieu. Asp Asp Lieu. Glin 53 O 535 54 O Pro Trp His Ser Phe Gly Ala Asp Ser Val Pro Ala Asn Thr Glu Asn 5.45 550 555 560 Glu Val Glu Pro Val Asp Ala Arg Pro Ala Ala Asp Arg Gly Lieu. Thir 565 st O sts Thr Arg Pro Gly Ser Gly Lieu. Thir Asn Ile Llys Thr Glu Glu Ile Ser 58O 585 59 O Glu Val Lys Met Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val 595 6OO 605 His His Glin Llys Lieu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys 610 615 62O Gly Ala Ile Ile Gly Lieu Met Val Gly Gly Val Val Ile Ala Thr Val 625 630 635 64 O Ile Val Ile Thr Lieu Val Met Leu Lys Llys Lys Glin Tyr Thr Ser Ile 645 650 655 His His Gly Val Val Glu Val Asp Ala Ala Val Thr Pro Glu Glu Arg 660 665 67 O His Leu Ser Lys Met Glin Glin Asn Gly Tyr Glu Asn Pro Thr Tyr Lys 675 68O 685

Phe Phe Glu Gln Met Glin Asn 69 O. 695

<210 SEQ ID NO 4 US 2009/029 1894 A1 Nov. 26, 2009 27

- Continued

<211 LENGTH: 39 &212> TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OO SEQUENCE: 4 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1. 5 1O 15 Lieu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Asn Gly 2O 25 Lieu Met Val Gly Gly Val Val 35

<210 SEQ ID NO 5 <211 LENGTH: 41 &212> TYPE: PRT <213> ORGANISM: Homo sapiens <4 OO SEQUENCE: 5 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1. 5 1O 15 Lieu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Asn Gly 2O 25 Lieu Met Val Gly Gly Val Val Ile Ala 35 4 O

<210 SEQ ID NO 6 <211 LENGTH: 42 &212> TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OO SEQUENCE: 6 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1. 5 1O 15 Lieu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Asn Gly 2O 25 Lieu Met Val Gly Gly Val Val Ile Ala Thr 35 4 O

What is claimed: 4. The method according to claim 1, wherein the leptin 1. A method for treating a progressive cognitive disorder, composition is a leptin mimic, or a pharmaceutically accept the method comprising the step of able salt thereof. (a) administering to a subject in need thereof a first com 5. The method according to claim 1, wherein the leptin position comprising composition is a leptin derivative, or a pharmaceutically (i) a phosphorylated tau accumulation-modulating amount acceptable salt thereof. 6. The method according to claim 1, wherein the leptin of a leptin composition, or a pharmaceutically accept composition is a leptin agonist, or a pharmaceutically accept able salt thereof, and able salt thereof. (ii) a pharmaceutically acceptable carrier, and 7. The method according to claim 1, wherein the phospho (b) modulating accumulation of phosphorylated tau in rylated tau accumulation modulating amount is an amount cerebrospinal fluid of the subject. from about 0.01 mg/kg body weight to about 100 mg/kg body 2. The method according to claim 1, wherein the progres weight. sive cognitive disorder is selected from the group consisting 8. The method according to claim 1, wherein the first of Alzheimer's Disease, progressive Supranuclear palsy, composition further comprises a second therapeutic agent. dementia, dementia pugilistica, Creutzfeldt-Jakob disease, 9. The method according to claim 8, wherein the second frontotemporal dementia, Pick's disease, and FTDP-17 (par therapeutic agent is at least one of an antibiotic, an anti-fungal kinsonism) corticobasal degeneration. agent, an antiviral agent, an anti-protozoal agent, a steroidal 3. The method according to claim 1, wherein the leptin anti-inflammatory agent, a non-steroidal anti-inflammatory composition is a leptin, or a pharmaceutically acceptable salt agent, an anti-oxidant; a hormone; a vitamin; an antihista thereof. mine agent, and a chemotherapeutic agent. US 2009/029 1894 A1 Nov. 26, 2009 28

10. The method according to claim 1, wherein the progres a leptin derivative, an AMP-dependent protein kinase activa sive disorder comprises accumulation of neurofibrillary tor, a leptin agonist, a leptin blocker, a mimic of a leptin tangles in brain. blocker, a leptin antagonist, an AMP-dependent protein 11. A method for improving resilience of cognitive func kinase inhibitor, orpharmaceutically acceptable salts thereof. tion in a subject in need thereof, the method comprising the 13. The method according to claim 11, wherein the leptin step of composition further comprises a second therapeutic agent. (a) administering to the Subject a composition comprising: 14. The method according to claim 13, wherein the second i.a cognitive function-enhancing amount of a leptin com therapeutic agent is at least one of an antibiotic, an anti-fungal position, and agent, an antiviral agent, an anti-protozoal agent, a steroidal ii. a pharmaceutically acceptable carrier; and anti-inflammatory agent, a non-steroidal anti-inflammatory (b) modulating accumulation of phosphorylated tau in agent, an anti-oxidant; a hormone; a vitamin; an antihista cerebrospinal fluid of the subject. mine agent, and a chemotherapeutic agent. 12. The method according to claim 11, wherein the leptin composition comprises at least one of a leptin, a leptin mimic, c c c c c