γ-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-beta peptide (A beta) found disproportionally in the cerebral plaques that characterize the disease. The serpentine presenilins are required for transmembrane cleavage of both the amyloid-P precursor protein (APP) and the Notch receptor by gamma -secretase, and presenilins are biochemically associated with the protease. Inhibitors of gamma -secretase have provided critical clues to the function of presenilins. Pharmacological profiling suggested that 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 presenilin appears to be the catalytic portion of a multi-protein gamma -secretase complex.