PROCESSING OF THE PRE-BETA-AMYLOID PROTEIN BY CATHEPSIN-D IS ENHANCEDBY A FAMILIAL ALZHEIMERS-DISEASE MUTATION

A major pre-beta-amyloid protein(695) (APP(695)) processing activity f rom Alzheimer's disease brain extracts was identified and found to be indistinguishable from the activity of cathepsin D.APP(695) processing activity cleaved APP(695) into a series of fragments that reacted on immunoblots to a monoclonal antibody (C286.8a) against beta-amyloid-(1 -7)-peptide and cleaved N-dansyl-APP-(591-601)-amide at the Glu-Val an d Met-Asp bonds. Fragments of 5.5 kDa and 10-12 kDa were formed from t he cleavage of APP(695) by cathepsin D at the Glu593-Va1594 bond, and had the same N-terminus as a minor form of beta-amyloid released by ce lls. The Lys595-->Asn and Met596-->Leu substitutions found in a pedigr ee of familial Alzheimer's disease, increased the cathepsin D-catalyze d rate of accumulation of 5.5 kDa and 10-12 kDa C286.8a-reactive fragm ents 5-10fold. This substitution also increased the rate of N-dansyl-A PP-(591-601)-amide cleavage at the Xaa-Asp bond by up to 41-fold. Thes e observations suggest a role of cathepsin D in beta-amyloid formation under certain circumstances.