{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:45:51Z","timestamp":1792043151661,"version":"4.4.0"},"reference-count":71,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u2010166127"],"award-info":[{"award-number":["PJT\u2010166127"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82293642"],"award-info":[{"award-number":["82293642"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82230043"],"award-info":[{"award-number":["82230043"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MedComm"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Mutations in Presenilin 1 (PS1) are the most common genetic cause of familial Alzheimer's disease (AD). However, the exact mechanisms by which these mutations alter amyloid precursor protein (APP) processing and drive amyloid \u03b2 (A\u03b2) production remain unclear. In this study, five PS1 mutations (M146V, G384A, C410Y, Y115H, and the Notch\u2010sparing mutation \u0394S169) were transfected into neuroblastoma cells lacking endogenous PS1\/PS2 expression and human embryonic kidney cells stably overexpressing either wild\u2010type APP or the APP Swedish mutation. We investigated the effects of these mutations on APP processing, A\u03b242\/A\u03b240 ratio, cytotoxicity, BACE1 expression, and PS1 endoproteolysis. Our results demonstrate that PS1 mutations differentially modulate APP processing, producing distinct A\u03b2 profiles independent of their effects on Notch signaling. All mutations increased the A\u03b242\/A\u03b240 ratio, while BACE1 levels were unchanged and no direct PS1\u2010BACE1 interactions were found. All mutations increased cytotoxicity, whereas only the Notch\u2010impairing mutations reduced cell viability, suggesting impaired Notch signaling may contribute to this effect. Lastly, the mutations exhibited distinct endoproteolytic rates that correlated only with APP\u2010C83 levels. These findings provide novel insights into how distinct PS1 mutations impact amyloid pathology.<\/jats:p>","DOI":"10.1002\/mco2.70978","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:48:43Z","timestamp":1790772523000},"source":"Crossref","is-referenced-by-count":0,"title":["Presenilin 1 Mutations Converge on A\u03b242\/A\u03b240 Elevation via Distinct Mechanisms"],"prefix":"10.1002","volume":"7","author":[{"given":"Isabel","family":"Bestard\u2010Lorigados","sequence":"first","affiliation":[{"name":"Department of Psychiatry Townsend Family Laboratories Graduate Program in Neuroscience The University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keenan","family":"Sterling","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Townsend Family Laboratories Graduate Program in Neuroscience The University of British Columbia  Vancouver 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