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

Mutations in the presenilin-1 (PSI) gene are associated with Alzheimer's disease 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 biological function of a naturally occurring PSI splice variant (PSI Delta exon8), which lacks the critical aspartate 257. Cell lines that stably express PS1 Delta exon8 or a PSI protein in which aspartate residue 257 is mutated secrete significant levels of A beta, whereas A beta generation is severely reduced in cells transfected with PSI containing a mutation of aspartate 385. In contrast, endoproteolytic processing of Notch is almost completely inhibited in cell lines expressing any of the PSI variants that lack one of the critical aspartates. These data indicate that PSI may differentially facilitate gamma-secretase-mediated generation of A beta and endoproteolysis of Notch.