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Neuroinflammation, mainly mediated by glial activation, plays an important role in AD progression. Although there is growing evidence for the anti-neuroinflammatory and neuroprotective effects of the cannabinoid system modulation, the detailed mechanism remains unclear. To address these issues, we analyzed the expression levels of cannabinoid receptor type II (\n                    <jats:italic>Cnr2\/Cb2<\/jats:italic>\n                    ) in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice and human AD precuneus, which is vulnerable to amyloid deposition in AD, and the effects of JWH 133, a selective CB2 agonist, on neuroinflammation in primary glial cells and neuroinflammation and cognitive impairment in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice. The levels of\n                    <jats:italic>Cnr2\/Cb2<\/jats:italic>\n                    were upregulated in microglia isolated from the cerebral cortex of\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice.\n                    <jats:italic>CNR2<\/jats:italic>\n                    expression was also increased in RNAs derived from human precuneus with advanced AD pathology. Chronic oral administration of JWH 133 significantly ameliorated the cognitive impairment of\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice without neuropsychiatric side effects. Microglia and astrocyte mRNAs were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, and the gene expression was determined by quantitative PCR. JWH 133 administration significantly decreased reactive astrocyte markers and microglial\n                    <jats:italic>C1q<\/jats:italic>\n                    , an inducer for the reactive astrocytes in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice. In addition, JWH133 administration inhibited the expression of p-STAT3 (signal transducer and activator of transcription 3) in astrocytes in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice. Furthermore, JWH 133 administration suppressed dystrophic presynaptic terminals surrounding amyloid plaques. In conclusion, stimulation of microglial CB2 ameliorates cognitive dysfunction in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL-G-F\/NL-G-F<\/jats:italic>\n                    <\/jats:sup>\n                    mice by controlling astrocyte activation and inducing beneficial neuroinflammation, and our study has implications that CB2 may represent an attractive therapeutic target for the treatment of AD and perhaps other neurodegenerative diseases involving neuroinflammation.\n                  <\/jats:p>","DOI":"10.1038\/s41419-024-07249-6","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T19:22:08Z","timestamp":1732562528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Microglial cannabinoid receptor type II stimulation improves cognitive impairment and neuroinflammation in Alzheimer\u2019s disease mice by controlling astrocyte activation"],"prefix":"10.1038","volume":"15","author":[{"given":"Akira","family":"Sobue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-7358","authenticated-orcid":false,"given":"Okiru","family":"Komine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumito","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Kakimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Miyoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noe","family":"Kawade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8038-7919","authenticated-orcid":false,"given":"Seiji","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Murayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1970-6903","authenticated-orcid":false,"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-9251","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-0035","authenticated-orcid":false,"given":"Koji","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"7249_CR1","doi-asserted-by":"crossref","unstructured":"2023 Alzheimer\u2019s disease facts and figures. 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