TARGETING OF CELL-SURFACE BETA-AMYLOID PRECURSOR PROTEIN TO LYSOSOMES - ALTERNATIVE PROCESSING INTO AMYLOID-BEARING FRAGMENTS

PROGRESSIVE cerebral deposition of the amyloid beta-peptide is an early and invariant feature of Alzheimer's disease. The beta-peptide is released by proteolytic cleavages from the beta-amyloid precursor protein (beta-APP) 1, a membrane-spanning glycoprotein expressed in most mammalian cells. Normal secretion of beta-APP involves a cleavage in the beta-peptide region 2,3, releasing the soluble extramembranous portion 4,5 and retaining a 10K C-terminal fragment in the membrane 6. Because this secretory pathway precludes beta-amyloid formation, we searched for an alternative proteolytic processing pathway that can generate beta-peptide-bearing fragments from full-length beta-APP. Incubation of living human endothelial cells with a beta-APP antibody revealed reinternalization of mature PAPP from the cell surface and its targeting to endosomes/lysosomes. After cell-surface biotinylation, full-length biotinylated beta-APP was recovered inside the cells. Purification of lysosomes directly demonstrated the presence of mature beta-APP and an extensive array of beta-peptide-containing proteolytic products. Our results define a second processing pathway for beta-APP and suggest that it may be responsible for generating amyloid-bearing fragments in Alzheimer's disease.