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Sleep disturbances hamper A\u03b2 production and clearance, thereby exacerbating the A\u03b2 burden. The mechanisms involved remain unclear. We reported that amyloid precursor protein (APP), the A\u03b2 source, possesses intracellular signaling that attenuates A\u03b2 production and prevents cognitive decline in AD mice. Our follow\u2010up study assessed whether enhancing APP\u2010mediated signaling affected sleep.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We expressed a membrane\u2010tethered APP intracellular domain (mAICD) and a variant lacking the G\u03b1\n                      <jats:sub>S<\/jats:sub>\n                      \u2010interacting site in AD mouse brains. Sleep patterns, cognitive behaviors, blood\u2013brain barrier (BBB) integrity, and gliosis were examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Sleep, BBB integrity, and memory were strongly correlated. mAICD expression rescued sleep and cognitive function impairments, prevented BBB leakage, and promoted astrocyte redistribution surrounding the neurovascular units in AD mice. G\u03b1\n                      <jats:sub>S<\/jats:sub>\n                      interaction with mAICD was critical.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>APP\u2010mediated signaling plays a key role in regulating sleep, maintaining BBB integrity, and preserving memory in AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71134","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T08:27:43Z","timestamp":1770107263000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["APP\u2010mediated intracellular signaling rescues sleep impairment and blood\u2013brain barrier leakage in Alzheimer's disease mouse model"],"prefix":"10.1002","volume":"22","author":[{"given":"Cl\u00e9mentine","family":"Puech","sequence":"first","affiliation":[{"name":"Department of Pediatrics School of Medicine University of Missouri  Columbia Missouri USA"},{"name":"Cl\u00e9mentine Puech, Group of Precision Medicine in Chronic Diseases. Hospital Nacional de Parapl\u00e9jicos. 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