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 nitric oxide (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