A SERINE-PROTEASE IN ALZHEIMERS-DISEASE CELLS CLEAVES A 16K-PEPTIDE WITH FLANKING RESIDUES UPSTREAM TO BETA-AMYLOID-N-TERMINUS AS NATURAL SUBSTRATE

A serine protease which cleaves an oligopeptide at the beta-amyloid (beta A4) N-terminus was identified and purified from extracellular fluid of familial Alzheimer's disease (FAD) lymphoblastoid cells. In order to search for a natural substrate that stands for a direct precursor of beta A4, C-terminal fragments of beta-amyloid precursor protein (APP) were prepared by immunoprecipitation of cytosol proteins with beta A4-specific antibody. The 16 kDa peptide with N-terminus 30 amino acids upstream from the beta A4-N-terminus, also existing in other hematopoietic cells, was proved to be a natural substrate for the protease in human lymphoid cells. Its cleaved fragment with beta A4N-terminus was thought to be less amyloidogenic on the basis of its property of self-aggregation in acidic pH. The results suggest the significance of the unique cleavage site at beta A4-upstreams in generation and accumulation of beta A4.