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We previously reported APP669\u2010711 as a novel A\u03b2\u2010related peptide detectable in human plasma and developed a composite biomarker that combines APP669\u2010711\/A\u03b21\u201042 and A\u03b21\u201040\/A\u03b21\u201042 ratios to serve as a plasma surrogate of cerebral A\u03b2 burden. We also identified ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin type 1 motif\u00a04) as an APP669\u2010cleaving enzyme that catalyzes the rate\u2010limiting step of APP669\u2010711 production. However, ADAMTS4 accounts for approximately 40% of APP669\u2010site cleavage, leaving the enzymes responsible for the remaining 60% unknown. Here, we identify ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin type 1 motif\u00a05) as a protease with stronger APP669\u2010site cleavage activity in\u00a0vitro. We further show that the difference in APP669\u2010site cleavage activity between ADAMTS4 and ADAMTS5 is explained by the regulation through the spacer (Sp) domain. Nonetheless, in\u00a0vivo experiments did not confirm a role for ADAMTS5 in plasma APP669\u2010711 production under healthy conditions. Because ADAMTS5 expression increases in certain pathological states, our results suggest that ADAMTS5 may contribute to plasma APP669\u2010711 production in AD patients with comorbid conditions.<\/jats:p>","DOI":"10.1096\/fj.202600043","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:15:16Z","timestamp":1774620916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of\n                    <scp>ADAMTS5<\/scp>\n                    as\n                    <scp>APP<\/scp>\n                    \u2010Cleaving Enzyme at the\n                    <scp>APP669<\/scp>\n                    Site"],"prefix":"10.1096","volume":"40","author":[{"given":"Miyabishara","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences The University of Tokyo  Tokyo 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