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Nature Cell Biology 2, 205–211 (1 April 2000) | doi:10.1038/35008626

Presenilin-1 differentially facilitates endoproteolysis of the |[bgr]|-amyloid precursor protein and Notch

Anja Capell , Harald Steiner , Helmut Romig , Simone Keck , Miriam Baader , Melissa G. Grim , Ralf Baumeister & Christian Haass

Mutations in the presenilin-1 (PS1) gene are associated with Alzheimer|[rsquo]|s disease and cause increased secretion of the neurotoxic amyloid-|[bgr]| peptide (A|[bgr]|). 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 PS1 splice variant (PS1 |[Delta]|exon 8), which lacks the critical aspartate 257. Cell lines that stably express PS1 |[Delta]|exon 8 or a PS1 protein in which aspartate residue 257 is mutated secrete significant levels of A|[bgr]|, whereas A|[bgr]| generation is severely reduced in cells transfected with PS1 containing a mutation of aspartate 385. In contrast, endoproteolytic processing of Notch is almost completely inhibited in cell lines expressing any of the PS1 variants that lack one of the critical aspartates. These data indicate that PS1 may differentially facilitate |[ggr]|-secretase-mediated generation of A|[bgr]| and endoproteolysis of Notch.