{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:27:18Z","timestamp":1788326838019,"version":"build-2803163510"},"reference-count":30,"publisher":"IMR Press","issue":"2","license":[{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81870832"],"award-info":[{"award-number":["81870832"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Beijing Committees of Education-Science Foundation of Beijing joint fund","award":["KZ202010025040"],"award-info":[{"award-number":["KZ202010025040"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) is characterized by the deposition of amyloid-\u03b2 peptide (A\u03b2) in the brain. A\u03b2 is produced by sequential \u03b2- and \u03b3-secretase cleavages of amyloid precursor protein (APP). Clinical trials targeting \u03b2- and \u03b3-secretases have all failed, partly because of the strong side effects. The aims of this work were to determine if the direct cleavage of APP by \u03b3-secretase inhibits A\u03b2 production, and to identify \u03b3-cleavage-inhibiting signals within APP that can be targeted to prevent A\u03b2 generation without inhibiting any enzyme. Methods: An APP mutant mimicking secreted APP\u03b3 was overexpressed in cells to test \u03b2-cleavage and A\u03b2 production. APP deletion and truncation mutants were overexpressed in cells to identify the \u03b3-secretase-inhibiting domain. The intracellular transport of the mutants was examined using immunofluorescence. Co-immunoprecipitation was performed to investigate the molecular mechanisms. Results: The APP N-terminal fragment mimicking the direct \u03b3-cleavage product was not cleaved by beta-secretase 1 to produce detectable A\u03b2. However, in cells, the C-terminal fragments of APP longer than the last 116 residues could not be cleaved by \u03b3-secretase in cells. No deletion mutant was cleaved by \u03b3-secretase. C99, the direct precursor of A\u03b2, was no longer a \u03b3-secretase substrate when green fluorescent protein was fused to its N-terminus. The large ectodomains prevented access to \u03b3-secretase. Conclusions: Enabling the direct \u03b3-cleavage of APP is a new and valid strategy to reduce A\u03b2. However, APP does not inhibit \u03b3-cleavage via a specific inhibitory sequence in the ectodomain. Other methods to fulfill the strategy may benefit AD prevention and therapy.<\/jats:p>","DOI":"10.31083\/j.fbl2902078","type":"journal-article","created":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T08:19:30Z","timestamp":1708676370000},"source":"Crossref","is-referenced-by-count":2,"title":["The Large Ectodomain of APP Prevents APP from being Directly Cleaved by \u03b3-Secretase"],"prefix":"10.31083","volume":"29","author":[{"given":"Yuan","family":"Li","sequence":"first","affiliation":[{"name":"The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hejie","family":"Li","sequence":"first","affiliation":[{"name":"The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenping","family":"Liang","sequence":"first","affiliation":[{"name":"The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"first","affiliation":[{"name":"The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"first","affiliation":[{"name":"The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Long JM, Holtzman DM. 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