The Role of Gamma-Secretase Modulators in Reducing ß-amyloid Plaque Formation in Patients with Alzheimer’s Disease

Courtney Welch

 Introduction.  Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, and the risk increases with age so that by age 85 some studies suggest that ∼50% of individuals will have the disease1,2. The pathological hallmarks of AD include the presence of senile plaques and neurofibrillary tangles (NFT).  Senile plaques are composed of aggregates of ß-amyloid (AB) peptides, which are generated by enzymatic cleavages of the amyloid precursor protein (APP)3.  Gamma-Secretase is a protease that cleaves APP to generate AB peptides that range in size from 36 to 42 amino acids.  A longer isoform, AB42, is predisposed to aggregation and can stimulate deposition and accumulation of AB peptides into toxic senile plaques4Methods.  A review of 3 studies using gamma-secretase modulators (GSMs) was done to analyze to pharmacodynamics in vitro and in vivo.  BIIB042, a brain-penetrant GSM, was applied to cell-based assays and was also fed orally to mice, rats and monkeys4.  BMS-932481 was tested in healthy young and elderly volunteers after single and multiple doses5.  NGP 555 is a GSM that was administered to transgenic mice, and normal rats6.  Each of these studies analyzed plasma and cerebrospinal fluid (CSF) levels of AB peptides following administration of the GSMs using ELISA and/or liquid chromatography with tandem mass spectrometry. Results.  BIIB042 reduced the levels of AB42 and increased the levels of AB38 in cell based assays, and in the plasma of mice, rats and monkeys.  BIIB042 reduced AB42 levels and AB plaque burden in Tg2576 mice, which serve as a model system for Alzheimer’s disease4.  BMS-932481 decreased CSF AB39, AB40, and AB42 while increasing AB37 and AB38. In plasma, reductions in AB40 and AB42 were observed. Although BMS-932481 was relatively safe and well tolerated after single-dose administrations, liver-related adverse effects after multiple-dose testing resulted in cessation of the study5. NGP 555 inhibited the production of AB42 and AB40 and caused an increase in the levels of AB38 and AB37.  Administration toTg2576 mice resulted in a significant reduction of amyloid plaques and significantly prevented cognitive deficits in Y-maze and Morris water maze performance tests6. Conclusions.  Targeting gamma-secretase to prevent the production and/or subsequent accumulation and aggregation of AB peptides has been a major focus of recent efforts in developing disease-modifying AD therapies4.  These results show pharmacodynamic activity in both animal and human studies and support a therapeutic rationale for continued evaluation of GSMs as disease modifying agents for patients with AD.

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