{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:41:33Z","timestamp":1791517293819,"version":"4.3.4"},"reference-count":59,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801088"],"award-info":[{"award-number":["81801088"]}],"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":["82471536"],"award-info":[{"award-number":["82471536"]}],"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":["32500517"],"award-info":[{"award-number":["32500517"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["2020JQ\u2010881"],"award-info":[{"award-number":["2020JQ\u2010881"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Glutamate\u2010mediated neurotoxicity is a key factor in the pathogenesis of Alzheimer's disease, yet its regulatory mechanism and connection to the amyloid \u03b2 (A\u03b2) cascade remain unclear. This study examined the role of the astrocytic A\u03b2 receptor, PirB, on glutamate reuptake, excitotoxic neuronal death, and cognition. In\u00a0vitro, primary astrocytes were treated with soluble PirB extracellular peptide (PEP), the PirB inhibitor Fluspirilene, or lentiviral vectors encoding PirB or shPirB. We measured excitatory amino acid transporter (EAAT) expression, intracellular glutamate levels, and calcium influx in astrocytes. We also evaluated neuronal apoptosis in neuron\u2013astrocyte co\u2010cultures. PirB inhibition (via PEP or Fluspirilene) significantly increased EAAT1 and EAAT2 expression and activated the mTOR signaling. This was accompanied by elevated astrocytic glutamate levels, decreased intracellular calcium, as well as reduced neuronal apoptosis, whereas PirB overexpression had the opposite effects. In\u00a0vivo, mice with astrocyte\u2010specific PirB conditional knockout (cKO) were injected with A\u03b2 oligomers into the hippocampus and subjected to cognitive behavioral assays. Hippocampal neuronal loss and apoptosis were evaluated through Nissl and TUNEL staining. PirB cKO mice showed enhanced exploratory behavior, improved working memory, and higher EAAT expression, along with higher Bcl\u20102\/Bax ratios, mTOR activation, and reduced neuronal apoptosis compared with A\u03b2\u2010injected PirB\n                    <jats:sup>flox\/flox<\/jats:sup>\n                    mice. Overall, our findings identify astrocytic PirB as a key driver of A\u03b2\u2010triggered glutamate\u2010mediated neurotoxicity and suggest that suppressing the PirB\u2010mTOR\u2010EAAT pathway could be a promising therapeutic strategy for mitigating A\u03b2\u2010related cognitive impairment.\n                  <\/jats:p>","DOI":"10.1002\/glia.70130","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T12:28:06Z","timestamp":1766406486000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Suppression of Astrocytic\n                    <scp>PirB<\/scp>\n                    Alleviates A\u03b2\u2010Induced Excitotoxicity and Cognitive Deficits via\n                    <scp>EAAT<\/scp>\n                    Expression"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7586-6082","authenticated-orcid":false,"given":"Xiaohua","family":"Zhang","sequence":"first","affiliation":[{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, the Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University  Wenzhou Zhejiang P. R. China"},{"name":"Shaanxi Key Laboratory of Brain Disorders &amp; Institute of Basic and Translational Medicine Xi'an Medical University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9708-462X","authenticated-orcid":false,"given":"Yuanjie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine Xi'an Medical University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5161-0210","authenticated-orcid":false,"given":"Xinlin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine Xi'an Jiaotong University Health Science Center  Xi'an P. R. 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