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In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic \u03b2\u2010amyloid peptide (A\u03b2). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and A\u03b2 in cells stably expressing human full\u2010length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation. Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9\u2010positive late endosomes (LE) to LAMP1\u2010positive lysosomes, which was paralleled by the enhanced LE\u2010lysosome fusion. In support, silencing of vacuolar protein sorting\u2010associated protein 41 (VPS41) that is implicated in LE\u2010lyso fusion prevented AP2S1\u2010mediated regulation of APP degradation and translocalization. In APP\/PS1 mice, an animal model of AD, AAV\u2010mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and A\u03b2, with the concomitant APP translocalization, LE\u2010lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE\u2010lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.<\/jats:p>","DOI":"10.1111\/tra.12874","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T10:22:18Z","timestamp":1669112538000},"page":"20-33","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp>AP2S1<\/scp> regulates <scp>APP<\/scp> degradation through late endosome\u2013lysosome fusion in cells and <scp>APP<\/scp>\/<scp>PS1<\/scp> mice"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1864-9978","authenticated-orcid":false,"given":"Qi\u2010Xin","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology  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