Following a lead provided by Gleevec, a team of U.S. researchers from The Rockefeller University and Intra-Cellular Therapies Inc. has identified a new regulatory protein, g-secretase activating protein, that activates g-secretase, a key Alzheimer's disease target.1
Because g-secretase activating protein (GSAP; PION) potentially regulates only the b-amyloid (Ab)-related activity of g-secretase, GSAP inhibitors might be safer than compounds that block all g-secretase activity. Intra-Cellular is developing small molecule compounds that can enter the brain and target GSAP.
g-Secretase is a proteolytic complex that converts amyloid-b (A4) precursor protein (APP) into Ab, the protein fragment that forms pathogenic amyloid plaques thought to underlie Alzheimer's disease (AD). Thus, one therapeutic avenue in AD has been to inhibit g-secretase to decrease Ab levels and prevent plaque-associated neuronal toxicity (see "Targeting GSAP in AD").
Despite the rationale, two small molecule g-secretase inhibitors have failed in their respective Phase III AD trials, at least in part because