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ECS is affected in neurodegenerative disorders, such as Alzheimer\u2019s disease (AD). Here we have evaluated the non-psychotropic endocannabinoid receptor type 2 (CB2) and lysophosphatidylinositol G-protein-coupled receptor 55 (GPR55) localization and expression during A\u03b2-pathology progression. Methods: Hippocampal gene expression of CB2 and GPR55 was explored by qPCR analysis, and brain distribution was evaluated by immunofluorescence in the wild type (WT) and APP knock-in AppNL-G-F AD mouse model. Furthermore, the effects of A\u03b242 on CB2 and GPR55 expression were assessed in primary cell cultures. Results: CB2 and GPR55 mRNA levels were significantly upregulated in AppNL-G-F mice at 6 and 12 months of age, compared to WT. CB2 was highly expressed in the microglia and astrocytes surrounding the A\u03b2 plaques. Differently, GPR55 staining was mainly detected in neurons and microglia but not in astrocytes. In vitro, A\u03b242 treatment enhanced CB2 receptor expression mainly in astrocytes and microglia cells, whereas GPR55 expression was enhanced primarily in neurons. Conclusions: These data show that A\u03b2 pathology progression, particularly A\u03b242, plays a crucial role in increasing the expression of CB2 and GPR55 receptors, supporting CB2 and GPR55 implications in AD.<\/jats:p>","DOI":"10.3390\/biology12060805","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T03:06:00Z","timestamp":1685588760000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Expression of the Endocannabinoid Receptors CB2 and GPR55 is Highly Increased during the Progression of Alzheimer\u2019s Disease in AppNL-G-F Knock-In Mice"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0342-1287","authenticated-orcid":false,"given":"Dina","family":"Medina-Vera","sequence":"first","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"},{"name":"Facultad de Ciencias, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjing","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China"},{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Bereczki","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rosell-Valle","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Shimozawa","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gefei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14152 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5795","authenticated-orcid":false,"given":"Fernando Rodr\u00edguez de","family":"de Fonseca","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6450-0870","authenticated-orcid":false,"given":"Per","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7000-7556","authenticated-orcid":false,"given":"Simone","family":"Tambaro","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ebiom.2016.03.035","article-title":"The Role of Amyloid-\u03b2 Oligomers in Toxicity, Propagation, and Immunotherapy","volume":"6","author":"Sengupta","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e10248","DOI":"10.15252\/emmm.201810248","article-title":"Inflammasomes in Neuroinflammatory and Neurodegenerative Diseases","volume":"11","author":"Voet","year":"2019","journal-title":"EMBO Mol. 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