γ-Secretase Inhibitors for the Treatment of Alzheimer's Disease

Alzheimer's disease is a neurodegenerative disorder manifested by cognitive and memory deterioration, impairment of language, and other activities of daily life. Two major pathological hallmarks are characteristics of Alzheimer's disease: intracellular neurofibrillary tangles and extracellular amyloid plaques. The amyloid plaque is mainly comprised of aggregated form of the 40-42 residue amyloid beta-peptide (A beta). The accumulation and deposition of A beta eventually lead to neuronal damage and cell death. A beta peptides are generated from a large precursor protein (APP) by beta-secretase (BACE) and gamma-secretase. Reduction of A beta by inhibition of gamma-secretase may prevent A beta-mediated downstream neurotoxic events, representing an attractive strategy to combat Alzheimer's disease. gamma-Secretase is a multi-component complex comprised of four distinct units: presenilin, nicastrin, aph-1, and pen2. In addition to processing APP, gamma-secretase has also been implicated in the cleavage of other substrates, the most notable one being the Notch receptor. Inhibition of Notch processing is the key factor of mechanism-based side effects associated with gamma-secretase inhibitors. It is imperative to balance the therapeutic efficacy and the risk of mechanism-based toxicity. Drug Dev Res 70: 94-100, 2009. (C) 2009 Wiley-Liss, Inc.