Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch

Mutations in the presenilin-1 (PSI) gene are associated with Alzheimer's di sease and cause increased secretion of the neurotoxic amyloid-beta peptide (A beta), Critical intramembraneous aspartates at residues 257 and 385 are required for the function of PS1 protein. Here we investigate the biologica l function of a naturally occurring PSI splice variant (PSI Delta exon8), w hich lacks the critical aspartate 257. Cell lines that stably express PS1 D elta exon8 or a PSI protein in which aspartate residue 257 is mutated secre te significant levels of A beta, whereas A beta generation is severely redu ced in cells transfected with PSI containing a mutation of aspartate 385. I n contrast, endoproteolytic processing of Notch is almost completely inhibi ted in cell lines expressing any of the PSI variants that lack one of the c ritical aspartates. These data indicate that PSI may differentially facilit ate gamma-secretase-mediated generation of A beta and endoproteolysis of No tch.