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Riluzole, a glutamate modulator approved for amyotrophic lateral sclerosis, reduces neuronal hyperexcitability, yet its in vivo effects on A\u03b2 oligomer\u2013induced cognitive dysfunction and glial alterations remain incompletely understood. Here, we investigated whether riluzole ameliorates A\u03b2\n                      <jats:sub>1-42<\/jats:sub>\n                      oligomer\u2013induced memory impairment and associated hippocampal pathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A\u03b2\n                      <jats:sub>1-42<\/jats:sub>\n                      oligomers were bilaterally microinjected into the dorsal CA1 region of freely moving male rats, followed by daily riluzole administration for 7 days. Then, the animals underwent a battery of behavioural tests before being sacrificed for immuno-histochemical studies. Glial engulfment of A\u03b2 and synapse was visualized through multiplex immunohistochemistry combined with super-resolution microscopy and three-dimensional (3D) reconstruction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Behavioral analyses revealed that riluzole significantly improved hippocampus-dependent memory, including contextual learning and spatial working memory, without affecting locomotor activity, anxiety-like behavior, or pain sensitivity. At the cellular level, riluzole reduced neuronal A\u03b2 accumulation which was strongly associated with improved learning performance across individual animals. It enhanced robust A\u03b2 internalization and lysosomal processing within astrocytes and microglia. Though A\u03b2-induced glial recruitment and activation persisted, riluzole enhanced morphological remodeling and shifted glial cells towards neuroprotective phenotype. Riluzole also attenuated A\u03b2-induced neuronal apoptosis, dendritic degeneration, and dendritic spine loss across the dorsal CA1 sublayers, and limited complement-mediated synaptic elimination by microglia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>By enhancing glial A\u03b2 clearance and preserving synaptic integrity, riluzole effectively counteracts A\u03b2-driven cognitive decline. Together, these findings highlight coordinated glial remodeling as a physiologically relevant mechanism at a therapeutically actionable stage of AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-026-03972-3","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T07:04:59Z","timestamp":1787641499000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Riluzole shifts glial responses to protect synapses and memory in A\u03b2 oligomer\u2013treated rats"],"prefix":"10.1186","volume":"23","author":[{"family":"Min-Kaung-Wint-Mon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Mitsushima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"5580","key":"3972_CR1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1126\/science.1072994","volume":"297","author":"J Hardy","year":"2002","unstructured":"Hardy J, Selkoe DJ. 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J Exp Med. 2019;216(7):1542\u201360. https:\/\/doi.org\/10.1084\/jem.20182386.","journal-title":"J Exp Med"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12974-026-03972-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-026-03972-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-026-03972-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T11:40:53Z","timestamp":1793533253000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12974-026-03972-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":91,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3972"],"URL":"https:\/\/doi.org\/10.1186\/s12974-026-03972-3","relation":{},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"assertion":[{"value":"16 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2026","order":6,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":7,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this article was revised: The revised supplementary materials have been updated","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Tissue or data from humans was not utilized in this study. All animal housing and surgical procedures followed the guidelines of the Institutional Animal Care and Use Committee of Yamaguchi University which comply with the Guide for the Care and Use of Laboratory Animals published by the National Institute of Health (NIH Publication No. 85\u2009\u2212\u200923, revised 1996). All experimental procedures were approved by the Institutional Animal Care and Use Committee of Yamaguchi University (No. 04-S02). The initial protocol was approved on 15 November 2013, and the final version of the protocol was updated on 6 November 2023. Our manuscript confirming the study was reported in accordance with ARRIVE guidelines (https:\/\/arriveguidelines.org).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"323"}}