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Recent studies demonstrated the dysregulation of the endocannabinoid (eCB) system (ECS) in AD brain. Here, we explored the possible alterations of ECS and the onset of gliosis in the retina of AD\u2010like mice. Tg2576 (TG) mice overexpressing the amyloid precursor protein (APP) were used at the age of 12\u2009months, when hippocampal \u03b2\u2010amyloid plaques had not been developed yet. Analysis of retinal gliosis showed a significant increase in the number of IBA1 (+) microglia cells in TG versus wild type (WT). Gliosis was not associated with retinal \u03b2\u2010amyloid plaques, evident retinal degenerative signatures, or excitotoxicity; instead, oxidative stress burden was observed as increased acrolein levels. Analysis of the ECS (receptors\/metabolic enzymes) through western blotting (WB) revealed the up\u2010regulation of cannabinoid receptor 2 (CB\n                    <jats:sub>2<\/jats:sub>\n                    ) and monoacylglycerol lipase (MAGL), the enzyme responsible for the degradation of 2\u2010arachidonoylglycerol (2\u2010AG), in TG retinas. Fluorescence intensity analysis of anti\u2010CB\n                    <jats:sub>2<\/jats:sub>\n                    and anti\u2010MAGL immuno\u2010stained cryosections was consistent with WB, showing their up\u2010regulation throughout the retinal layers. No statistically significant differences were found for the other enzymes\/receptors of the ECS under study. However, linear regression analysis for individual animals showed a significant correlation between CB\n                    <jats:sub>2<\/jats:sub>\n                    and fatty acid amide hydrolase (FAAH), diacylglycerol lipase \u03b1\/\u03b2 (DAGL\u03b1\/\u03b2), and APP; instead, a significant negative correlation was found between MAGL and APP. Finally, ultra\u2010performance liquid chromatography\u2013tandem mass spectrometry (UPLC\u2013MS\/MS) demonstrated a significant reduction of 2\u2010AG in TG retinas (~0.34\u2009ng\/mg) compared to WT (~1.70\u2009ng\/mg), while a trend toward increase was found for the other eCB anandamide (AEA). Overall, our data indicate that gliosis and ECS dysregulation\u2014in particular of CB\n                    <jats:sub>2<\/jats:sub>\n                    , MAGL and 2\u2010AG\u2014occur in the retina of AD\u2010like mice before retinal degeneration and development of hippocampal \u03b2\u2010amyloid plaques.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16256-fig-0008-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16256","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T12:18:36Z","timestamp":1731932316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Alterations of endocannabinoid signaling and microglia reactivity in the retinas of\n                    <scp>AD<\/scp>\n                    \u2010like mice precede the onset of hippocampal \u03b2\u2010amyloid plaques"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8592-2412","authenticated-orcid":false,"given":"Annamaria","family":"Tisi","sequence":"first","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences University of L'Aquila  L'Aquila Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Scipioni","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical 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Meo","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences University of L'Aquila  L'Aquila Italy"},{"name":"Department of Veterinary Medicine University of Teramo  Teramo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakthimala","family":"Palaniappan","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences University of L'Aquila  L'Aquila Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco Della","family":"Valle","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Technology for Food, Agriculture and Environment University of Teramo  Teramo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Fanti","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Technology for Food, Agriculture and Environment University of Teramo  Teramo 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