Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

Abstract

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by A β peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ -secretase is critical for A β production, many in the biopharmaceutical community focused on γ -secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ -secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic A β peptides without affecting other γ -secretase substrates, the epsilon ( ε ) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ -secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of A β 42 . Multiple chemical classes of γ -secretase modulators have been identified which differ in the pattern of A β peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from A β 42 and other highly amyloidogenic A β peptides to shorter and less neurotoxic forms of the peptides without altering the total A β pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity.