Cleavage of a beta-amyloid precursor sequence by cathepsin D.

Abstract

The identify of the proteases that release beta-amyloid, found in the senile plaques of Alzheimer's disease, from its precursor APP, have not been rigorously identified. As senile plaques contain lysosomal enzymes, and production of some of the amyloidogenic intermediates are inhibited by lysosomotrophic agents, it has been suggested that cathepsins are involved in amyloidogenesis. A synthetic 31-residue peptide overlapping the beta-secretase cleavage site is found to be digested at two mutually exclusive sites, one and three residues on the N-terminal side of the N-terminal Asp residue of beta-amyloid. Coupled with the action of aminopeptidases, lysosomal or endosomal cathepsin D could be responsible for generating the N-terminus of beta-amyloid in vivo.