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Here, we identify \u03b11-antitrypsin (AAT) as a previously unrecognized modulator of cannabinoid receptor 2 (CB2R)-associated signaling in \u03b1-syn pathology. An acute transcriptomic screen revealed prominent induction of the\n                    <jats:italic>Serpina1<\/jats:italic>\n                    gene family, while primary-microglial and chronic AAV\u2013\u03b1-syn experiments showed that\n                    <jats:italic>Cnr2<\/jats:italic>\n                    deficiency amplified\n                    <jats:italic>Serpina1<\/jats:italic>\n                    \/AAT responses, consistent with an insufficient compensatory reaction to persistent inflammation. Molecular docking, reciprocal co-immunoprecipitation, and surface plasmon resonance provided complementary evidence supporting an AAT\u2013CB2R association under the respective assay conditions. Functionally, AAT reduced the \u03b1-syn-associated elevation of intracellular cAMP in an AM630-sensitive manner and attenuated ATP-evoked Ca\n                    <jats:sup>2<\/jats:sup>\n                    \u207a responses, calpain-1 activity, GSK-3\u03b2 N-terminal cleavage, and NLRP3\/caspase-1-related cytokine production; these effects were substantially diminished in\n                    <jats:italic>Cnr2<\/jats:italic>\n                    -deficient microglia. Calpeptin reproduced key molecular effects, implicating calpain-related proteolysis in this neuroimmune response. In vivo, intracerebroventricular AAT preserved NAc synaptic ultrastructure, ameliorated excitatory synaptic abnormalities in dopamine D2 receptor-expressing medium spiny neurons, and improved fear-memory retrieval, spontaneous alternation, and anxiety-like behavior, without affecting novel object recognition or motor performance. Several effects were attenuated under\n                    <jats:italic>Cnr2<\/jats:italic>\n                    -deficient conditions, although selected electrophysiological responses persisted. Our findings identify AAT\u2013CB2R-linked signaling as a modulator of microglial inflammatory homeostasis and support the therapeutic potential of AAT for NLRP3-associated neuroinflammation and non-motor dysfunction in \u03b1-synucleinopathies.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00583-5","type":"journal-article","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T08:15:01Z","timestamp":1789892101000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b11-Antitrypsin attenuates microglial NLR family pyrin domain containing 3 inflammasome activation via cannabinoid receptor 2 signaling to ameliorate \u03b1-synucleinopathy-related behavioral deficits"],"prefix":"10.1186","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1676-5695","authenticated-orcid":false,"given":"Linjuan","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3929-7633","authenticated-orcid":false,"given":"Hsuan","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weipin","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9947-3821","authenticated-orcid":false,"given":"Yanping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9511-6986","authenticated-orcid":false,"given":"Xiaodong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"issue":"1","key":"583_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00501-z","volume":"16","author":"S Koga","year":"2021","unstructured":"Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW. 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