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Despite decades of research, mechanisms of amyloidogenic APP processing remain highly controversial. Here, we show that in neurons, APP processing and A\u03b2 production are controlled by the protein complex\u20102 (AP\u20102), an endocytic adaptor known to be required for APP endocytosis. Now, we find that AP\u20102 prevents amyloidogenesis by additionally functioning downstream of BACE1 endocytosis, regulating BACE1 endosomal trafficking and its delivery to lysosomes. AP\u20102 is decreased in iPSC\u2010derived neurons from patients with late\u2010onset AD, while conditional AP\u20102 knockout (KO) mice exhibit increased A\u03b2 production, resulting from accumulation of BACE1 within late endosomes and autophagosomes. Deletion of BACE1 decreases amyloidogenesis and mitigates synapse loss in neurons lacking AP\u20102. Taken together, these data suggest a mechanism for BACE1 intracellular trafficking and degradation via an endocytosis\u2010independent function of AP\u20102 and reveal a novel role for endocytic proteins in AD.<\/jats:p>","DOI":"10.15252\/embr.201947954","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T03:50:44Z","timestamp":1587613844000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["AP\u20102 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons"],"prefix":"10.1038","volume":"21","author":[{"given":"Sujoy","family":"Bera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Camblor\u2010Perujo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Calleja Barca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Negrete\u2010Hurtado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Racho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"De Bruyckere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Wittich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Ellrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7894-6539","authenticated-orcid":false,"given":"Soraia","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Adjaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3425-6659","authenticated-orcid":false,"given":"Natalia L.","family":"Kononenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"BFEMBR201947954_CR1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","volume":"297","author":"J Hardy","year":"2002","unstructured":"Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. 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