The processing of Alzheimer A4/beta-amyloid protein precursor: identification of a human brain metallopeptidase which cleaves -Lys-Leu- in a model peptide.

A search for human brain peptidases with the specificity to cleave the 695 residue A4/beta amyloid precursor protein within the -Gln-Lys-Leu- (611-613) sequence was carried out using carbobenzoxy-Gln-Lys-Leu-p-nitroanilide as substrate. A metalloendopeptidase was identified in the soluble fraction of post mortem human cerebral cortex which cleaves the substrate at the Lys-Leu bond. The enzyme was partially purified by anion exchange and size exclusion chromatography; it has a Mr of approximately 105-120 kda, is inhibited by EDTA but can be reactivated by Mn++ ions, and has maximum activity between pH 6.8 and 8.