Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1

The beta-amyloid precursor protein (beta-APP), which is involved in the pat hogenesis of Alzheimer's disease, and the Notch receptor, which is responsi ble for critical signalling events during development, both undergo unusual proteolysis within their transmembrane domains by unknown gamma-secretases , Here we show that an affinity reagent designed to interact with the activ e site of gamma-secretase binds directly and specifically to heterodimeric forms of presenilins, polytopic proteins that are mutated in hereditary Alz heimer's and are known mediators of gamma-secretase cleavage of both beta-A PP and Notch. These results provide evidence that heterodimeric presenilins contain the active site of gamma-secretase, and validate presenilins as pr incipal targets for the design of drugs to treat and prevent Alzheimer's di sease.