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 Aβpeptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Sinceγ-secretase is critical for Aβproduction, many in the biopharmaceutical community focused onγ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to controlγ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβpeptides without affecting otherγ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators ofγ-secretase activity have been discovered that spare theεcleavage of APP and other substrates while decreasing the production of Aβ42. Multiple chemical classes ofγ-secretase modulators have been identified which differ in the pattern of Aβpeptides produced. Ideally, modulators will allow theεcleavage of all substrates while shifting APP cleavage from Aβ42and other highly amyloidogenic Aβpeptides to shorter and less neurotoxic forms of the peptides without altering the total Aβpool. Here, we compare chemically distinct modulators for effects on APP processing andin vivoactivity.
In vivo measurement of widespread synaptic loss and associated tau accumulation in early Alzheimer’s disease