The type II transmembrane serine protease matriptase cleaves the amyloid precursor protein and reduces its processing to {beta} amyloid [Enzymology]

Recent studies have reported that many proteases, besides the canonical α-, β- and γ-secretases, cleave the amyloid precursor protein (APP) and modulate β amyloid (Aβ) peptide production. Moreover, specific APP isoforms contain Kunitz protease inhibitor (KPI) domains, which regulate the proteolytic activity of serine proteases. This prompted us to investigate the role of matriptase, a member of the type II transmembrane serine protease family, in APP processing. Using qRTPCR, we detected matriptase mRNA in several regions of the human brain, with an enrichment in neurons. RNA-seq data of human dorsolateral prefontal cortex revealed relatively high levels of matriptase RNA in young individuals while lower levels were detected in older individuals. We further demonstrate that matriptase and APP directly interact with each other and that matriptase cleaves APP at a specific arginine residue (Arg-102) both in vitro and in cells. Site-directed (Argto-Ala) mutagenesis of this cleavage site abolished matriptase-mediated APP processing. Moreover, we observed that a soluble, shed matriptase form cleaves endogenous APP in SH-SY5Y cells and that this cleavage significantly reduces APP processing to Aβ40. In summary, this study identifies matriptase as an APP cleaving enzyme, an activity that could have important consequences for the abundance of Aβ and in Alzheimer's disease pathology.

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