Matriptase Cleaves the Amyloid-Beta Peptide 1–42 at Arg-5, Lys-16, and Lys-28

The type-II transmembrane extracellular serine protease matriptase was shown to cleave at Arg-102 in the amino-terminal region of the amyloid precursor protein (APP). In this study we determined matriptase cleavage sites in the amyloid-beta (Aβ) peptide region of APP (Asp-597 to Ala-638 in the APP695 isoform). A recombinant human matriptase protease domain was used to cleave a synthetic human Aβ1–42 peptide. The human APP695 or mutants at the candidate matriptase cleavage sites was co-expressed with the human matriptase or its protease-dead mutant in HEK293 cells to evaluate matriptase cleavage of APP. Overexpression of matriptase in the M17 human neuroblastoma cells was performed to determine the effect of matriptase expression on endogenous APP.