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Aside from full\u2010length A\u03b2 peptides starting with an aspartate residue in position 1, both N\u2010terminally truncated and elongated A\u03b2 peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N\u2010terminally truncated A\u03b24\u2013x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N\u2010terminally elongated A\u03b2 peptides.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used cell\u2010free and cell\u2010based assays in combination with matrix\u2010assisted laser desorption\/ionisation time\u2010of\u2010flight mass spectrometry (MALDI\u2010TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N\u2010terminally elongated A\u03b2 peptide variants. Antibodies against these A\u03b2 variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N\u2010terminal to Asp\u2010(1) in the A\u03b2 peptide sequence between residues Glu\u2010(\u20107) and Ile\u2010(\u20106) as well as Glu\u2010(\u20104) and Val\u2010(\u20103), resulting in the release of N\u2010terminally elongated A\u03b2\u20106\u2010x and A\u03b2\u20103\u2010x peptides, of which the latter serve as a component in a promising A\u03b2\u2010based plasma biomarker. A\u03b2\u20106\/\u20103\u201040 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of A\u03b2\u20106\/\u20103\u2010x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N\u2010terminally elongated A\u03b2\u20106\/\u20103\u2010x peptides.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The current findings implicate ADAMTS4 in both the pathological process of A\u03b2 peptide aggregation and in the early detection of amyloid pathology in AD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12991","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T03:06:03Z","timestamp":1718247963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Amino\u2010terminally elongated A\u03b2 peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease 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