European Review for Medical and Pharmacological Sciences 2012; 16: 1651-1664 Current therapeutic strategy in Alzheimer’s disease

S. SINGH, A.S. KUSHWAH, R. SINGH, M. FARSWAN*, R. KAUR**

Pharmacology and Toxicology Research Laboratory, ASBASJS Memorial College of Pharmacy Bela, Ropar (Punjab), India *Department of Pharmaceutical Sciences SBS (PG), Institute of Biomedical Sciences and Research, Balawala, Dehradun, India **Rayat Institute of Pharmacy, Railmajra, Punjab, India

Abstract. – Alzheimer’s disease (AD) is a both clinical medicine and basic research to un- chronic, progressive, neurodegenerative disorder cover the pathogenesis of the brain degeneration that places a substantial burden on patients, their and, ultimately, develop therapeutic interventions families, and society. Alzheimer’s disease (AD) is that prevent or slow progression of Alzheimer’s the sixth leading cause of all deaths in the United States, and the fifth leading cause of death in disease. Alzheimer’s disease (AD) is a challeng- Americans aged 65 and older. During the past ing neurodegenerative disorder in elderly causing years, several agents have been approved that en- dementia characterized clinically by progressive hance cognition and global function of AD pa- memory loss and other cognitive impairments. tients, and recent advances in understanding AD The research in AD is expanding exponentially pathogenesis has led to the development of nu- and currently aiming at clinical, cellular molecu- merous compounds that might modify the disease process. A wide array of antiamyloid and neuropro- lar, genetics and other therapeutic research ap- 1 tective therapeutic approaches are under investi- proaches . AD is not simply short memory loss gation on the basis of the hypothesis that amyloid but also results in other cognitive symptoms such beta (Aβ) protein plays a pivotal role in disease on- as memory loss, disorientation, confusion, prob- set and progression and that secondary conse- lems with reasoning and thinking and behavioral quences of Aβ generation and deposition, includ- ing tau hyperphosphorylation and neurofibrillary symptoms such as agitation, anxiety, delusions, tangle formation, oxidation, inflammation, and exci- depression, hallucinations, insomnia and wander- totoxicity, contribute to the disease process. Inter- ing. Neuropathologically, presence of extra neu- ventions in these processes with agents that re- ronal plaques and intraneuronal neurofibrillary duce amyloid production, limit aggregation, or in- tangles two characteristic lesions in post-mortem crease removal or vaccination and immunization brain, where as clinically generalized progressive might block the cascade of events comprising AD 2 pathogenesis. Reducing tau hyperphosphoryla- dementia are the major hallmarks of AD . In- tion, limiting oxidation and excitotoxicity, and con- creased neuronal iron in an active redox state, in- trolling inflammation might be beneficial disease- creased (NO) synthesis in microglia modifying strategies. Potentially neuroprotective and abnormalities in mitochondrial genome are and restorative treatments such as neurotrophins, assumed as additional contributory sources. Also neurotrophic factor enhancers, and stem cell-relat- lipid peroxidation (LPO) a hallmark of oxidative ed approaches are also under investigation. tissue injury has been found to be elevated in the 3 Key Words: AD brain . An understanding of these underlying Alzheimer’s disease, Inflammation, Hyperphospho- mechanisms will certainly form the basis for de- rylation, Neuroprotection. vising better strategies for diagnosis, prevention and treatment. During the last couple of years, much has been learned about factors that may Introduction contribute to the onset of AD3.

Nearly a century has passed since Alois Alzheimer provided his meticulous description of Antiamyloid Approaches the impaired cognitive performance and neu- ropathological analysis of his patient “Auguste”. Proteolytic processing enzymatically of trans- His observations still guide expanding efforts in membrane amyloid precursor protein (APP)

Corresponding Author: Sarabjeet Singh, MD; e-mail: [email protected] 1651 S. Singh, A.S. Kushwah, R. Singh, M. Farswan, R. Kaur forms Aβ peptides. According to amyloid hy- with IgG has been tested in a preliminary clinical pothesis these Aβ peptides initiate the process trial16. This novel approach in current theme of leading to neuronal dysfunction and death in pa- research and further detailed studies of this ap- tient suffering from AD. No anti-amyloid treat- proach are planned. ment options are currently available, but several are under active investigation. β-Secretase Inhibitors β-Secretase, a member of the pepsin family, is Vaccination and Immunization Therapies a membrane-anchored aspartyl protease17. Aβ is Studies so far have shown that passive transfer generated from APP by β and γ-secretase-medi- of Aβ monoclonal antibodies from vaccinated ated cleavage. The therapeutic potential of β-sec- mice to AD model mice reduced cerebral amy- retase inhibition, with limited mechanism-based loidosis4,5. Such effects are suggested to be medi- toxicity, has been suggested by studies conducted ated at least partially by reactive microglia that in β-site APP cleaving enzyme 1 (BACE-1) became activated to engulf antibody decorated knockout mice, which were shown to produce Aβ via Fc receptor mediated phagocytosis4. Pas- much less Aβ from APP18,19. Injection of the β- sive transfer of Aβ-antibodies discouraged the secretase inhibitor KMI-429 into the hippocam- active immunization which is potentially unsafe pus of APP transgenic mice significantly reduced and damages autoaggresive CD4+T cells re- Aβ production in vivo20. Development of β-sec- sponse to show aseptic meningoencephalitis in a retase inhibitors is challenging because of con- small percentage of patients. So, passive immu- straints of the active site; however, several small nization has emerged as alternative to active im- molecule agents are under active investigation21. munization4. The first efficacy analysis conduct- ed in a small subset of AN1792-treated patients γ-Secretase Inhibitors showed antibodies generated against Aβ and sig- Reductions in Aβ levels in the brain, cere- nificantly slower rates of decline in cognitive brospinal fluid (CSF), and plasma have been re- function and activities of daily living6. Recent ported in rodents treated with the γ-secretase in- studies of using combinations in 3X TG AD hibitors DAPT22-24. Acute treatment with DAPT at mouse model reported amelioration of behavioral a dose that reduced Aβ concentrations in the brain deficits clearance of cerebral amyloidosis and re- attenuated cognitive impairment in a transgenic duction of soluble hyperphosphorylated tau pro- mouse model of AD, with no effect on perfor- teins7,8. AN 1792 may have provoked brain in- mance in controls25. This study suggested that flammation in a small subset of treated individu- cognitive impairments in AD might be associated als owing to the use of pro-inflammatory Th-1 with Aβ, potentially in advance of plaque forma- adjuvant (QS-21)9. tion, and might be reversible with acute pharma- However, Aβ vaccine with a full length 1-40 cologic treatment. In a randomized, controlled administered by a different route (intranasal clinical trial conducted in 70 patients with mild to route) produced significant Aβ antibodies tities moderate AD, plasma Aβ 1-40 decreased by 38% and have effectively reduced cerebral Aβ /plaque with administration of LY450139 di-hydrate for 6 levels in the PDAAP mouse model10,11. The anti- weeks, whereas CSF Aβ1-40 levels showed no bodies, thus, produced were largely of IgG1 and significant change26. Treatment with the γ-secre- IgG2b isotypes widely recognized as the B- cells tase inhibitor was well-tolerated. Further investi- epitopes. Studies in which transcutaneous Aβ gation is needed to determine whether higher dos- vaccination with a full length of Aβ along with es will yield more beneficial changes in Aβ con- cholera-toxin to PSAPP mouse model where centrations without an increase in toxicity. Safety brain to blood efflux was noted and reduction of in γ-secretase inhibitor trials is closely scrutinized cerebral Aβ levels by 50% have been reported. because agents with limited selectivity might af- Furthermore, no induction of micro hemorrhage fect proteins beyond Aβ-related γ-secretase, such and nil aseptic inflammation which were earlier as Notch, and might have deleterious effects on reported after passive Aβ immunization in AD the gastrointestinal tract, thymus, and spleen27. mice were observed12-14. Several trials with pas- sive immunization or vaccination with selective γ-Secretase Modulators Aβ monoclonal antibodies are underway15. Im- Chronic CHF5074 treatment reduced brain b- munoglobulin G (IgG) contains anti-Aβ antibod- amyloid burden, associated microglia inflamma- ies, and passive immunization of AD patients tion and attenuated spatial memory deficit in

1652 Current therapeutic strategy in Alzheimer’s disease hAPP mice. This novel γ-secretase modulator is a lization agents are planned. Other small molecule promising therapeutic agent for Alzheimer’s dis- inhibitors of Aβ aggregation (scylloinositol; ease. In epidemiologic investigations, traditional AZD-103) have been identified36. These stabilize nonsteroidal anti-inflammatory drugs (NSAIDs) Aβ in non-toxic non-fibrillar complexes. They have been associated with a significantly reduced rescue long-term potentiation in transgenic mice risk of AD28. Negative findings from recent con- and reverse the memory deficit in rats observed trolled clinical trials of individual NSAIDs sug- after intra ventricular Aβ infusion. This method gest that protection against AD is not a benefit has promise for acute improvement in AD as provided by the entire class29. Tarenflurbil (MPC- well as reduction of the chronic effects of Aβ. 7869) modulates γ-secretase to produce less of the Apolipoprotein E4 is an established risk factor toxic form of Aβ (Aβ42) and more of the nontoxic for AD and might exert its effect through enhanc- shorter length peptide. Tarenflurbil reduces Aβ ing Aβ aggregation. Small molecules that alter production by human cells and reduces plaque the conformational structure of E4 to mimic E3 burdens in transgenic mouse modules of AD30. might ameliorate the E4 effect and are being as- A phase II trial of tarenflurbil conducted in 207 sessed for their therapeutic potential37. patients with mild or moderate AD showed no overall benefit after 12 months of treatment31. In Statins (Inhibitors of subgroup analyses, patients with mild AD who re- Cholesterol Biosynthesis) ceived the highest dose and had the highest blood A gene that is associated with AD is levels of the drug exhibited a significant benefit in apolipoprotein E (APOE), which encodes for the activities of daily living and global function. Fur- lipid-binding protein APOE. This gene has three thermore, an analysis of adverse events showed a allelic variants: APOE2, APOE3 and APOE4. In- delay of almost a year in the onset of behavioral dividuals who have one or two copies of APOE4 symptoms in the patients receiving tarenflurbil are at higher risk for AD, whereas carriers of the when compared with the placebo-treated group32. APOE2 allele have a lower risk compared with An ongoing phase III study is further testing the the general population. Epidemiological studies, potential utility of this agent. which indicate that there might be a connection between high cholesterol levels during mid-life Antifibrillization Agents and an increased risk of AD later in life. More- Strategies targeting the fibrillary aggregates of over, people taking statins drugs that inhibit cho- Aβ protein are being explored. In neuronal cell lesterol biosynthesis have a remarkably reduced cultures, the sulfated glycosaminoglycan mimet- risk of developing AD38,39. These drugs are wide- ic tramiprosate (NC-531) was found to maintain ly used and are safe for long-term treatment, so Aβ in a non-fibrillar form and reduce Aβ42-in- the possibility that they might prevent or delay duced cell death33. In transgenic mice, the onset of AD has generated considerable ex- tramiprosate treatment significantly reduced citement. Adding a further connection to the amyloid plaque load and soluble and insoluble amyloid hypothesis, rabbits that were fed choles- Aβ40 and Aβ42 levels in brain. In a 3-month, terol had elevated brain Aβ levels and developed double-blind stage of a phase II trial conducted amyloid plaques. Furthermore, mammalian cells in 58 patients with mild to moderate AD, that were treated with statins produced much less tramiprosate-treated patients exhibited dose-de- Aβ 65,66 with similar results being observed in pendent reductions in CSF Aβ42 levels 34-35. the plasma and cerebrospinal fluid of guinea pigs Treatment appeared to be well-tolerated, with no given high doses of statins40. Although the mole- reports of serious adverse events. Nausea and cular mechanism of the effect of the statins on vomiting were the most common side effects and Aβ production is unclear, they might alter the occurred in 10% to 12% of patients. Results from ability of all three major secretases to cleave the open-label extension of this trial suggested APP. Processing by α-secretase is apparently in- slowing of cognitive decline in patients with mild creased, whereas depletion of cholesterol inhibits disease who were treated for up to 36 months. γ-secretase activity in buoyant membrane micro Two randomized, double-blind, placebo-con- domains. trolled, 18-month, phase III clinical trials are un- It is possible that modulation of cholesterol derway in North America and Europe to further levels might change membrane fluidity to affect evaluate the safety and efficacy of this treatment these membrane-associated proteases and their in mild to moderate AD. Trials of other antifibril- APP substrates, and/or that changes in choles-

1653 S. Singh, A.S. Kushwah, R. Singh, M. Farswan, R. Kaur terol might affect Aβ deposition or clearance. In- tion and Aβ metabolism might help explain the terestingly, by blocking the conversion of free benefit of PPAR-γ agonists; reductions in insulin cholesterol to cholesterol esters results in similar levels might liberate IDE to metabolize Aβ. effects on Aβ production in cell culture41,42. This Rosiglitazone-treated animals exhibited improved process is carried out by acyl-coenzyme A: cho- spatial learning and memory abilities when com- lesterol acyltransferase (ACAT) as part of the pared with controls. In a preliminary randomized, regulation of cholesterol homeostasis. Pharmaco- double-blind, placebo-controlled study conducted logical inhibition or genetic mutation of ACAT in 30 individuals with mild AD or amnestic mild results in a reduction of total Aβ as well as cognitive impairment (MCI), patients receiving Aβ42, indicating that the effects of cholesterol rosiglitazone exhibited better cognitive perfor- on APP processing might be mediated through mance on selected instruments after 4 and 6 months cholesterol esters, although a role for a more di- than patients receiving placebo53. AD subjects with- rect effect of free cholesterol cannot be ruled out. out an APOE e4 allele showed significant improve- A substantially reduced risk of AD has been re- ment with rosiglitazone compared with those with ported in some (but not all) observational studies of E4. No change from baseline plasma Aβ levels was statins (3-hydroxy-3-methylglutaryl coenzyme A observed with rosiglitazone treatment at 6 months, reductase inhibitors) used for the treatment of dys- but decreases were seen with placebo, suggesting a lipidemia43,44 . The effect of statins on AD might not beneficial impact on disease progression. A second be mediated by their cholesterol-lowering proper- study found a similar response profile limited to ties. Rather, they might decrease Aβ by increasing those without the E4 genotype, Pioglitazone, anoth- processing of APP through the γ-secretase path- er PPAR-γ-agonist, is also in clinical trials for mild- way45,46. In a recent randomized, double-blind, moderate AD54,55. Insulin itself might improve placebo-controlled pilot study in 63 individuals memory in AD. Craft56 demonstrated that intranasal with normal cholesterol levels and mild to moderate insulin resulted in improvement in delayed recall in AD, atorvastatin provided some clinical benefit af- AD and MCI subjects. ter treatment periods of 6 months and 1 year47. However, several trials found no association with Metal-Protein Attenuating Compounds statin use and subsequent AD onset or cognitive de- Aβ and APP interact with the biometals , cline48,49. Underscoring the need for further research copper, and iron, indicating these metals play a with careful attention to study design and method- role in Aβ aggregation and cytotoxicity57. Metal- ology. The U.S. National Institute on Aging (NIA) protein attenuating agents such as clioquinol were is sponsoring the Cholesterol Lowering Agent to tested to determine their effects on Aβ activity in Slow Progression (CLASP) of AD study to investi- animal and human studies. A study of APP trans- gate the safety and effectiveness of simvastatin in genic mice treated with clioquinol showed a 49% slowing progression in patients with mild to moder- decrease in Aβ brain deposition after 9 weeks, ate AD. Industry-sponsored, large phase III studies without systemic toxicity58. Clioquinol was associ- of atorvastatin in patients with mild to moderate ated with subacute myelo-opticoneuropathy when AD are ongoing as well. administered as a systemic antibiotic in Japan in the 1950s to 1970s; studies of this drug were Peroxisome Proliferator-Activated closely monitored for potential toxic effects. A pi- Receptor Agonists lot phase II clinical trial in 36 patients with moder- Insulin abnormalities and insulin resistance ately severe AD suggested that clioquinol might might contribute to the neuropathology and clinical inhibit Aβ aggregation and reduce Aβ-related ox- symptoms of AD50. Transgenic mice fated to devel- idative injury59. However, the statistically signifi- op AD-type pathology are more likely to develop cant effects in this trial were observed only in the insulin resistance and have impaired regulation of more severely affected subgroup of patients and insulin and glucose levels with age than wild-type were not maintained by the 36 week end point. mice51. The thiazolidinedione rosiglitazone increas- Other metal chelators are being designed and test- es peripheral insulin sensitivity through its effects ed in preclinical studies and clinical trials. A on peroxisome proliferator-activated receptor-gam- lipophilic metal chelator, molecule-XH1, with ma (PPAR). In transgenic mouse brain, rosiglita- amyloid-binding and metalchelating moieties, re- zone has been shown to attenuate reductions in in- duced APP protein expression in human cells and sulin-degrading enzyme (IDE) mRNA and decrease attenuated brain Aβ amyloid pathology in APP Aβ42 levels52. IDE’s dual role in insulin degrada- transgenic mice60. The lipophilic metal chelator

1654 Current therapeutic strategy in Alzheimer’s disease

DP-109 markedly reduced amyloid plaque burden for advanced glycation end products (RAGE) re- in brains in APP transgenic mice61 and epigallo- sides in cells of the blood vessel walls and trans- catechin-3-gallate, the main polyphenol con- ports Aβ across the blood-brain barrier. Inhibi- stituent of green tea, which has metal-chelating tion of the RAGE-ligand interaction reduces Aβ and radical-scavenging properties, produced sig- accumulation in the brains of transgenic mice68. nificant reductions in iron-regulated APP and Aβ RAGE is a target for drug development. peptide in cell cultures62. Peripheral Sink Approaches M1 Muscarinic Agonists Gelsolin (GMI) has high affinity for peripheral The M1 subtype of muscarinic acetylcholine Aβ, and administration of this agent results in bind- receptors potentially plays a role in AD via sev- ing of serum Aβ with creation of a “sink” pulling eral mechanisms, including effects on Aβ pep- Aβ from brain to blood69. This approach might lead tide, tau hyperphosphorylation, and cholinergic to reduced brain amyloidosis in humans. Some vac- function63. The M1 muscarinic agonist AF267B cination strategies are also achieved through “sink” increased non-amyloidogenic APP processing in mechanisms. The Nogo-66 receptor (NgR) is a re- vitro and decreased brain Aβ levels in vitro and ceptor for myelin inhibitor proteins and participates in vivo64. In a recently developed Alzheimer’s in limiting brain injury related axonal growth. mouse model characterized by both plaques and There is an inverse correlation between Aβ levels tangles, AF267B administration attenuated Aβ and NgR levels within the brain70. Administration and tau pathologies in the hippocampus and cor- of peripheral NgR reduces Aβ in the transgenic tex and improved some cognitive deficits65. Sig- mouse brain, increases serum Aβ, and improves nificant reductions in CSF Aβ were reported with spatial memory71. Such approaches might be of val- the selective M1 agonist talsaclidine in a ran- ue in humans with AD, and drug development tar- domized, double-blind, placebo controlled study geting this mechanism is underway. in 40 patients with AD66. Past studies with the M1 agonist xanomeline demonstrated limited Neuroprotective approaches cognitive and behavioral effects in AD patients67. Aβ appears to exert some of its neurotoxic ef- Receptor for Advanced Glycation end fects through numerous secondary pathways, in- Products-Related Mechanisms cluding tau hyperphosphorylation and neurofibril- Several molecules have been identified that af- lary tangle formation, oxidation, inflammation, fect brain Aβ through mechanisms not included demyelination, and excitotoxicity. These processes in the previously described classes. The receptor are potential targets for neuroprotective therapies.

Table I. Drugs under clinical trial for the treatment of Alzheimer’s disease.

Bapineuzumab-AAB001 Phase III Binds and removes Aβ-peptide CAD 106 II/IIa/IIb Immunotherapy AC1204 Phase II/III Targets glucose hypo metabolism by providing ketone bodies as alternative source Acc-001 II/IIa/IIb Antibody vaccine Affitope AD02/Mimotope Aβ (16) II/IIa/IIb Aβ (1-6) immunotherapy α-Tochopherol phase III Destroys toxic free radicals AZD 1446/TC-6683 II/IIa/IIb Nicotinic (nAChR) receptor activator BMS-708163 II/IIa/IIb γ-secretases inhibitor CERE-110/Nerve Growth Factor Gene Therapy II/IIa/IIb May reduce cholinergic cell loss in AD Dimebon Phase III NMDA Inhibitor DHA/Omega 3 fatty acid Phase III Modulation of presenilin ELND005 Phase II/III Prevent Aβ-oligomeric formation I.V. Immunoglobulin/IvIg Phase III Reduces Aβ and improves cognition MABT5102A Phase I Binds and remove Aβ that accumulates in brain Nicotinamide II/IIa/IIb Inhibitor of sirtuins PBT2 II/IIa/IIb Inhibits oligomeric formation disaggregates plaques and neutralizes Aβ-toxicity PF-04494700/TTP488 II/IIa/IIb RAGE-inhibitor (receptor for advanced glycation end products)

1655 S. Singh, A.S. Kushwah, R. Singh, M. Farswan, R. Kaur

Antioxidants individuals with AD than in age-matched con- Oxidative injury is a common cause of cellular trols82,83. Among dementia-free elderly individu- injury or death. Studies in a transgenic model of als participating in the Framingham study, devel- AD suggested that oxidative stress might be an im- opment of AD was greater in participants with portant early event in the pathogenesis of disease72. elevated homocysteine concentrations than those Conflicting results have been reported in longitudi- without elevations84. Evidence from APP trans- nal studies of the putative free-radical scavenger α- genic mice suggested that increased homocys- tocopherol (vitamin E) in dementia-free elderly teine might. hinder DNA repair in neurons, ren- populations73. In a cross-sectional, prospective dering them vulnerable to Aβ-induced damage study of dementia in elderly individuals in Cache and a recent study in mice found that increased County, Utah, use of vitamin E and vitamin C sup- homocysteine levels might exert toxic effects on plements in combination was associated with re- brain micro vessels and disrupt the blood-brain duced prevalence and incidence of AD74. In re- barrier85,86. A federally sponsored clinical trial of search conducted by the Alzheimer Disease Coop- homocysteine lowering vitamin combinations is erative Study, the effects of vitamin E, selegiline (a now in progress. monoamine oxidase B [MAO-B] inhibitor), the two agents in combination and placebo were compared Anti-Inflammatory Agents on time to death, time to nursing home placement, Certain Non-Steroidal Anti-Inflammatory progression to severe dementia, or a defined severi- Drugs (NSAIDs) have been shown to modulate ty of impairment of activities of daily living in pa- γ-secretase activity in mammalian cells and in tients with moderate AD75. After adjusting for the mice87. NSAIDs alter the specificity of γ-secre- severity of baseline cognitive impairment, there tase, decreasing the production of Aβ42 and in- were significant delays in the onset of at least one creasing the production of a shorter form of Aβ of these four outcomes with vitamin E, selegiline, that terminates at residue 38. So, although the or combination therapy versus placebo after 2 mechanism by which these compounds affect γ- years. In a recent double-blind study in patients secretase is unclear – for example, direct versus with MCI, there were no significant differences be- indirect effects their ability to reduce Aβ42 se- tween groups receiving vitamin E or placebo in the lectively and the fact that they are already known probability of progression to AD76. Several other to be safe for human use has spurred plans for antioxidants, including curcumin, are under investi- their use in clinical trials for the prevention gation77-79. Concerns about cardiovascular risk of and/or treatment of AD. Processing of APP by α- vitamin E have emerged, and the risk/benefit ratio secretase does not lead to Aβ production. How- of high dose vitamin E is being reexamined. ever, stimulation of α-secretase mediated pro- cessing of APP reduces Aβ formation, presum- Astrocyte-Modulating Agents ably by shunting more APP down this alternative The observation that Aβ plaques are surround- pathway. Such stimulation can be accomplished ed by activated astrocytes that produce reactive by the activation of protein kinase C (PKC); for oxygen and nitrogen species suggests that astro- example, by treatment with phorbol esters. More cyte activation might have a role in the pathogen- practically, PKC can be activated by muscarinic esis of AD. In a rodent ischemia model, arundic M1- and M3-receptor agonists and such agents acid (ONO-2506) decreased infarct size and im- are considered reasonable candidates for AD proved neurologic outcome80. The astrocyte- therapy. Potential problems with this strategy modulating agent protected dopaminergic neu- might be undesirable side effects as a conse- rons against neurotoxicity in a mouse model of quence of the chronic activation of muscarinic Parkinson’s disease and prevented motor abnor- receptors88-92. The first demonstration that mus- malities by modulating astrocytic activation81. carinic agents can modulate APP processing93,94. The astrocyte-modulating compound ONO-2506 Although microscopic evidence of inflammation is undergoing assessment in a phase II clinical has been observed in the brains of patients with trial of patients with mild to moderate AD. AD95, a series of controlled clinical trials demon- strated no significant benefit with prednisone96, Homocysteine-Lowering Strategies diclofenac97 rofecoxib98, nimesulide99, or naprox- Concentrations of the sulfur-containing amino en in slowing the rate of decline in AD. In a re- acid homocysteine, previously associated with cent double-blind study of patients with MCI, ro- cardiovascular risk are reported to be higher in fecoxib did not significantly delay the diagnosis

1656 Current therapeutic strategy in Alzheimer’s disease of AD or improve cognitive or global function100. fast synaptic neurotransmission in the brain. An A disease-modifying effect of anti-inflammatory investigation in mice demonstrated glutamate agents is plausible but not supported by currently AMPA receptor involvement in the regulation of available clinical trial data. Potential benefits of sensorimotor, affective, and cognitive func- these agents must be weighed against risk of side tions107. Positive AMPA receptor modulators effects including gastrointestinal bleeding. might have utility in a broad spectrum of neuro- logic pathologies, with tests in preclinical models NMDA-Receptor Antagonists suggesting potential neuroprotective effects and Cognitive decline in patients with AD has enhanced cognitive performance108-112. In a dou- been linked with neuronal damage from excite ble-blind, placebo-controlled, phase II trial, the toxicity caused by persistent over activation of efficacy and safety of the AMPA receptor modu- NMDA receptors by glutamate. Both Aβ and lator CX516 were evaluated in 175 patients with over expression of tau proteins, appear to be trig- MCI113. The CX516 treatment group did not gers for the excessive activation of NMDA (N- demonstrate significant improvement in delayed methyl-D-aspartate) receptors and the resulting recall of a 15-item list compared with the place- excite toxic pathway that leads to cell death101,102. bo group after 4 weeks of treatment. A subset The NMDA receptor antagonist , ap- analysis showed that the patients with the worst proved by the Food and Drug Administration baseline memory impairment exhibited improve- (FDA) for the treatment of moderate to severe ment in the delayed recall test with CX516 ver- AD, might reduce glutaminergic excitotoxicity sus placebo. A significant difference in patient and provide symptomatic improvement by affect- withdrawals was observed between the CX516 ing neuronal function in the hippocampus103. A and placebo groups, primarily related to gastroin- randomized, double-blind, placebo controlled testinal side effects, but no treatment-related seri- phase III study conducted in the U.S. in patients ous adverse events were reported in either group. with moderate to severe AD showed significant Further development of this class of compounds improvement with memantine (20 mg/day) ver- is warranted. sus placebo in activities of daily living and neu- ropsychological outcomes104. No clinically rele- Tau-related Therapies vant differences were observed in the safety pro- Phosphorylation of tau proteins, critical for the files of memantine and placebo. In a second U.S. production of intracellular neurofibrillary tan- controlled clinical trial, memantine administered gles, is dependent on Intracellular kinases such in combination with the cholinesterase inhibitor as glycogen synthase kinase 3 (GSK3) Lithium donepezil in patients with moderate to severe AD has been shown to reduce hyperphosphorylation was also associated with significantly increased of tau proteins by inhibiting GSK3 in cell culture cognitive function, decreased decline in activities and in transgenic mice114-116. Through its in- of daily living, and decreased incidence of new hibitory actions on GSK3, lithium also blocks the behavioral symptoms when compared with accumulation of Aβ peptides in the brains of placebo105. Other NMDA receptors, including mice that overproduce APP117. (MRZ 2/579), have demonstrated This agent could prove beneficial by reducing neuroprotective potential in preclinical investiga- the formation of both neurofibrillary tangles and tions and are proceeding to clinical develop- amyloid plaques, but its toxicity in older adults ment106 . In a double-blind, randomized, placebo- might limit its use. A second mood stabilizer, val- controlled phase II clinical trial conducted in 198 proic acid, has been reported to inhibit GSK3, and patients with moderate to severe AD, patients re- there is an ongoing NIA sponsored trial of val- ceiving neramexane therapy for 24 weeks had proic acid in mild to moderate AD. Tau hyper significantly greater improvement in activities of phosphorylation and formation of intracellular daily living compared with patients receiving neurofibrillary tangles might be the principal cell placebo. However, no significant difference was death pathway in AD. Inhibitors of this process demonstrated in measures of cognitive function. might be necessary to complement effects of anti- amyloid therapies. For example, a recent report AMPA-Receptor Modulators demonstrated that transgenic mice with cerebral Glutamate activation of alpha-amino-3-hy- amyloidosis demonstrate a reduction in behavioral droxy-5-methyl- 4-isoxazole-propionic acid deficits when tau levels are lowered, without a (AMPA) receptors is believed to mediate most concomitant lowering of the cerebral amyloid bur-

1657 S. Singh, A.S. Kushwah, R. Singh, M. Farswan, R. Kaur den. Drug discovery efforts are underway to iden- Cholinesterase Inhibitors tify viable therapeutic tau-modulating candidates. Cholinesterase inhibitors augment cholinergic function in AD at the postsynaptic cholinergic neu- Caspase Inhibitors ron. This pharmaceutical class reduces acetyl- Caspase enzymes might represent an impor- cholinesterase-induced destruction of acetylcholine tant link between amyloid plaques and neurofib- in the synaptic cleft, increases the intrasynaptic rillary tangles in AD as well as being critical to residence time of acetylcholine, and facilitates in- cell death pathways. Neurons treated with Aβ teraction between acetylcholine and the postsynap- peptide activate caspases, which trigger cleavage tic cholinergic receptor. Cholinesterase inhibitors of tau and produce truncated forms of the pro- are used primarily as long-term symptomatic treat- teins that rapidly and extensively assemble into ment for AD. Evidence derived from clinical tri- abnormal filaments characteristic of the tangles als129, imaging130 and basic science studies suggest found in AD118. Caspase activation is also re- that cholinesterase inhibitors might reduce APP quired for apoptosis in forebrain neurons119 and processing and provide some degree of neuropro- is increased in the brains of patients with tection131-135. AD120,121. Exposure of cortical cell cultures to a Most long-term clinical observations indicate caspase-3 inhibitor blocked caspase-induced the principal effect of cholinesterase inhibitors is cleavage of tau122. In addition, caspase inhibitors symptomatic treatment with limited disease mod- have prevented neuronal damage or loss in ani- ifying activity136. mal models of head injury and stroke suggesting this approach might have utility in the treatment of AD123,124. Neuroprotective and Neurorestorative Approaches Nicotine Acetylcholine Receptor Agonists There are significant losses of some nicotine Nerve growth factor (NGF) is a member of the acetylcholine receptor (nAChR) subtypes on neu- neurotrophin family of polypeptides. Other mem- rons in the hippocampus and temporal cortex of bers of this protein family exhibit similarities in patients with AD, concurrent with significant in- structure and function and include neurotrophin- creases in the number of astrocytes and astro- 3 (NT-3), neurotrophin-4 (NT-4), and brain-de- cytes expressing the 7 nAChR subtype. The in- rived neurotrophic factor (BDNF). Each of these creased expression of 7 nAChRs on astrocytes is growth factors plays an important role in normal positively correlated with the number of neuritic neural development and maintenance of the ma- plaques, suggesting a potentially important role ture central and peripheral nervous systems, in- for this receptor subtype in disease pathogenesis. cluding mediation of neuronal proliferation, dif- Nicotine treatment of transgenic mice that over ferentiation, and neuronal survival137 NGF, like express Aβ with nicotine results in a reduction in other neurotrophins, promotes cell survival by cortical Aβ levels with short-term administration signaling through specific tyrosine kinase recep- and a reduction in amyloid plaque formation and tors, thereby engaging internal cellular machin- 7 nAChR expression with long-term administra- ery to effectively block apoptosis from occurring tion125 In animal models, nicotine produces en- in either a developing or damaged neurons. Giv- hanced performance on working memory en their survival-promoting properties, neu- tasks126. Galantamine, a cholinesterase inhibitor rotrophins are considered potential therapeutic with nicotinic modulating properties, reduces agents for neurodegenerative disease138. Specifi- APP metabolism in an animal model of AD127. cally for AD, evidence from studies in mice sug- The 4-2 nAChR partial agonist (TC- gests that NGF might play a significant role in 1734) has demonstrated memory-enhancing maintaining neuronal integrity, as well as sur- properties in rat and mouse models, neuroprotec- vival in response to injury of the basal choliner- tive effects in studies in cultures and hippocam- gic forebrain neurons A lack of endogenous NGF pal slices, and a positive safety/tolerability pro- can lead to memory deficits, whereas NGF ad- file in phase I clinical studies128. Phase II studies ministration rescues neurons from injury-induced showed some improvement in cognitive function cell damage and leads to associated memory im- in ispronicline-treated patients with age-associat- provements139,140. Hence, NGF and NGF-related ed memory impairment and MCI; additional agents might have neurorestorative as well as phase II studies in AD patients are underway. neuroprotective properties. The impermeability

1658 Current therapeutic strategy in Alzheimer’s disease of the blood-brain barrier to exogenous NGF and 3) SUBBARAO KV, RICHARDSON JS, ANG LC. Autopsy sam- other neurotrophins presents a significant chal- ples of Alzheimer’s cortex show increased peroxi- lenge for evaluation of potential therapeutic ben- dation in vitro. J Neurochem 1990; 55: 342-345. 4) BARD F, C ANNON C, BARBOUR R, BURKE RL, GAMES D, efits in AD. Strategies to circumvent this trans- GRAJEDA H, GUIDO T, H U K, HUANG J, JOHNSON- port challenge are the surgical implantation of WOOD K, KHAN K, KHOLODENKO D, LEE M, LIEBERBURG NGF-expressing cells (eg, gene therapy)141 or ad- I, MOTTER R, NGUYEN M, SORIANO F, V ASQUEZ N, ministration of agents that or potentiate the en- WEISS K, WELCH B, SEUBERT P, S CHENK D, YEDNOCK T. dogenous production of NGF and other neu- Peripherally administered antibodies against 142,143 amyloid beta-peptide enter the central nervous rotrophins . The nonpeptidic agent xalipro- system and reduce pathology in a mouse model den (SR-57746), a neurotrophic factor enhancer of Alzheimer disease. Nat Med 2000; 6: 916-919. (NTFE), demonstrates neurotrophic effects in 5) DEMATTOS RB, BALES KR, CUMMINS DJ, DODART JC, several preclinical neurodegenerative in vivo and PAUL SM, HOLTZMAN DM. Peripheral anti-A betaan- in vitro models144. Xaliproden activates endoge- tibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse nous neurotrophin synthesis, including NGF and model of Alzheimer's disease. Proc. Natl. Acad. 145 BDNF, in rat cortical astrocytes . In a rat model Sci USA 2001; 98: 8850-8855. of the forebrain cholinergic neuron and memory 6) HOCK C, KONIETZKO U, STREFFER JR, TRACY J, SIG- deficits of AD, xaliproden reversed hippocampal NORELL A, MÜLLER-TILLMANNS B. Antibodies against choline acetyltransferase reduction (a measure of beta-amyloid slow cognitive decline in cellular activity and viability) and decreased be- Alzheimer’s disease. Neuron 2003; 38: 547-554. 146 7) ODDO S, BILLINGS L, KESSLAK JP, CRIBBS DH, LAFERLA FM. havioral disturbances . Magnetic resonance Abeta immunotherapy leads to clearance of early, imaging demonstrated the neuroprotective effects but not late, hyperphosphorylated tau aggregates of xaliproden in this model Ongoing randomized, via the proteasome. Neuron 2004; 43: 321-332. controlled, phase III trials are currently assessing 8) ODDO S, VASILEVKO V, C ACCAMO A, KITAZAWA M, CRIBBS effects of this agent on cognitive and global func- DH, LAFERLA FM. Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cog- tions in patients with mild to moderate AD Cere- nitive decline in transgenic mice with plaques and brolysin (FPF 1070), a peptide mixture with neu- tangles. J Biol Chem 2006; 281: 39413-39423. rotrophic activity, enhances synaptic regenera- 9) CRIBBS DH, GHOCHIKYAN A, VASILEVKO V, T RAN M, tion, reduces Aβ deposition, and ameliorates per- PETRUSHINA I, SADZIKAVA N, BABIKYAN D, KESSLAK P, formance deficits in APP transgenic mice147. KIEBER-EMMONS T, C OTMAN CW, AGADJANYAN MG. Ad- juvant-dependent modulation of Th1 and Th2 re- Randomized, double-blind, placebo controlled sponses to immunization with betaamyloid. Int Im- studies show that cerebrolysin infusions signifi- munol 2003; 15: 505-514. cantly improve activities of daily living and cog- 10) LEMERE CA, MARON R, SPOONER ET, GRENFELL TJ, nitive function148,149. Reported rates of adverse MORI C, DESAI R, HANCOCK WW, WEINER HL, SELKOE events are similar across treatment and placebo DJ. Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amy- groups. Targeted delivery of human NGF by loid burden in PD-APP mice. Ann NY Acad Sci gene transfer prevents injury-induced degenera- 2000; 920: 328-331. tion of cholinergic neurons in adult mon- 11) WEINER HL, LEMERE CA, MARON R, SPOONER ET, GREN- keys150,151. In a recent phase 1 study, genetically FELL TJ, MORI C, ISSAZDEH S, HANCOCK WW, SELKOE modified, autologous fibroblasts producing hu- DJ. Nasal administration of amyloidbeta peptide man NGF were implanted into the forebrains of decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol 2000; six patients with mild AD. After an average fol- 48: 567-579. low-up period of 22 months, no long-term post- 12) MARINARO M, STAATS HF, HIROI T, J ACKSON RJ, COSTE surgical adverse events occurred, and the rate of M, BOYAKA PN, OKAHASHI N, YAMAMOTO M,KIYONO H, cognitive decline appeared to be ameliorated. BLUETHMANN H, FUJIHASHI K, MCGHEE JR. 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