gamma-secretase inhibitors as molecular probes of presenilin function

Mutations in the presenilins cause Alzheimer's disease (AD) and alter gamma -secretase activity to increase the production of the 42-residue amyloid-b eta peptide (A beta) found disproportionally in the cerebral plaques that c haracterize the disease. The serpentine presenilins are required for transm embrane cleavage of both the amyloid-P precursor protein (APP) and the Notc h receptor by gamma -secretase, and presenilins are biochemically associate d with the protease. Inhibitors of gamma -secretase have provided critical clues to the function of presenilins. Pharmacological profiling suggested t hat gamma -secretase is an aspartyl protease, leading to the identification of two conserved aspartates important to presenilin's role in proteolysis. Conversion of transition-state analogue inhibitors of gamma -secretase to affinity reagents resulted in specific tagging of the heterodimeric form of presenilins, strongly suggesting that the active site of gamma -secretase lies at the interface of the presenilin heterodimer. Heterodimeric presenil in appears to be the catalytic portion of a multi-protein gamma -secretase complex.