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Metabotropic glutamate receptor 5 (mGluR5) is expressed ubiquitously in the brain and is a key molecule in regulating synaptic transmission and plasticity. It has been shown that mGluR5 is elevated in astrocytes in Alzheimer's disease. However, it remains elusive how astrocytic mGluR5 contributes to the pathogenesis of Alzheimer's disease.<\/jats:p>\n                  <jats:p>Here, we first quantified a high expression level of astrocytic mGluR5 in the hippocampus of Alzheimer's disease brains and demonstrated that the expression of astrocytic mGluR5 was positively correlated with Alzheimer's disease progression in both humans and mice. Upregulating astrocytic mGluR5 in the CA1 region at an early stage accelerated, whereas downregulating these receptors rescued, amyloid-\u03b2 (A\u03b2) pathology and cognitive impairment in Alzheimer's disease mice. Moreover, the activation of mGluR5 led to calcium hyperactivity in astrocytes, causing A\u03b2 pathology progression due to dysregulated A\u03b2 uptake and degradation in astrocytes. Importantly, attenuating astrocytic calcium hyperactivity in the hippocampal CA1 region in the prodromal phase ameliorated A\u03b2 pathology and cognitive defects in Alzheimer's disease mice.<\/jats:p>\n                  <jats:p>Our findings thus reveal a fundamental contribution of astrocytic mGluR5 in presymptomatic Alzheimer's disease that may serve as a potential diagnostic and therapeutic target for early Alzheimer's disease pathogenesis.<\/jats:p>","DOI":"10.1093\/brain\/awaf186","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T08:13:30Z","timestamp":1747210410000},"page":"134-149","source":"Crossref","is-referenced-by-count":7,"title":["Astrocytic mGluR5-dependent calcium hyperactivity promotes amyloid-\u03b2 pathology and cognitive impairment"],"prefix":"10.1093","volume":"149","author":[{"given":"Tianqi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]},{"name":"Nanhu Brain-Computer Interface Institute, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University , Hangzhou 311100 ,","place":["China"]},{"name":"NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]},{"name":"Nanhu Brain-Computer Interface Institute, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University , Hangzhou 311100 ,","place":["China"]},{"name":"NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiwei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]},{"name":"NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanli","family":"Wu","sequence":"additional","affiliation":[{"name":"National Health and Disease Human Brain Tissue Resource Center, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]},{"name":"NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangshuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Core Facilities, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou 310052 ,","place":["China"]},{"name":"Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education , Hangzhou 310052 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Dong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Nanhu Brain-Computer Interface Institute, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University , Hangzhou 311100 ,","place":["China"]},{"name":"NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University , Hangzhou 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-4734","authenticated-orcid":false,"given":"Yi","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of General Intensive Care Unit of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]},{"name":"NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University , Hangzhou 310058 ,","place":["China"]},{"name":"National Health and Disease Human Brain Tissue Resource Center, Zhejiang University School of Medicine , Hangzhou 310058 ,","place":["China"]},{"name":"Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education , Hangzhou 310052 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"2026010812425777900_awaf186-B1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"2026010812425777900_awaf186-B2","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer disease: An update on pathobiology and treatment 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