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(12) Patent Application Publication (10) Pub. No.: US 2009/0291894 A1 Tezapsidis Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0291894 A1 Tezapsidis Et Al 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) GREENBERGCorrespondence 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.
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