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However, the underlying mechanisms are still unclear. Here, we revealed that A\u03b2 increased the expression level of synaptic adhesion molecule protocadherin\u2010\u03b3C5 (Pcdh\u2010\u03b3C5) in a Ca<jats:sup>2+<\/jats:sup>\u2010dependent manner, associated with aberrant elevation of synapses in both A\u03b2\u2010treated neurons in\u00a0vitro and the cortex of APP\/PS1 mice in\u00a0vivo. By using <jats:italic>Pcdhgc5<\/jats:italic> gene knockout mice, we demonstrated the critical function of Pcdh\u2010\u03b3C5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh\u2010\u03b3C5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh\u2010\u03b3C5 in the brain of APP\/PS1 mice was knocked down by shRNA. Downregulation of Pcdh\u2010\u03b3C5 efficiently rescued neuronal hyperactivity and impaired cognition in APP\/PS1 mice. Our findings revealed the pathophysiological role of Pcdh\u2010\u03b3C5 in mediating A\u03b2\u2010induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16066-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16066","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T08:54:00Z","timestamp":1706950440000},"page":"1060-1079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Synaptic adhesion molecule protocadherin\u2010\u03b3C5 mediates \u03b2\u2010amyloid\u2010induced neuronal hyperactivity and cognitive deficits in Alzheimer's disease"],"prefix":"10.1111","volume":"168","author":[{"given":"Min","family":"Su","sequence":"first","affiliation":[{"name":"Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erying","family":"Xuan","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyi","family":"Sun","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine Xiamen University  Xiamen Fujian 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