{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:35:48Z","timestamp":1790994948128,"version":"4.1.0"},"reference-count":100,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jazz Pharmaceutics UK (formerly GW)"},{"name":"University College Dublin"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer\u2019s disease (AD). We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APPswe\/PS1dE9 (APP\/PS1) mice. In wild-type (WT) slices from C57BL6 mice, acute treatment with CBDA (10 \u03bcM) did not alter levels of hippocampal long-term potentiation (LTP); however, it did reverse the attenuation of LTP produced by acute beta amyloid peptide (A\u03b242). We also examined the effects of CBDA or vehicle in APP\/PS1 mice and WT littermates over a 5-week period at 8 months. LTP levels recorded in slices from WT mice treated with CBDA at 1, 10, or 30 mg\/kg (IP) or vehicle were similar. LTP was attenuated in slices from vehicle-treated APP\/PS1 compared to vehicle-treated WT mice, while treatment of APP\/PS1 mice with all doses of CBDA reversed the deficits in LTP. There was also a deficit in paired-pulse facilitation (PPF) in vehicle-treated APP\/PS1 compared to WT, indicating altered synaptic function and transmitter release; this was reversed in slices from CBDA-treated APP\/PS1 mice. Levels of cortical soluble A\u03b242 were similar across CBDA- and vehicle-treated groups; however, the level of aggregated A\u03b242 was decreased in the CBDA-treated group. Proteomic analysis of cortical tissue from APP\/PS1 cortex compared to WT revealed alterations in protein expression, with pathway enrichment analyses suggesting implicated canonical pathways, including mitochondrial dysfunction, protein sorting, and synaptogenesis; all were significantly improved by CBDA treatment. These changes likely facilitate the improvement in synaptic transmission and LTP we observed following CBDA treatment in APP\/PS1 mice. This research suggests that CBDA should be considered a novel therapy for AD.<\/jats:p>","DOI":"10.3390\/ijms26104944","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T09:58:22Z","timestamp":1747821502000},"page":"4944","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer\u2019s Disease: An Electrophysiological and Proteomic Analysis"],"prefix":"10.3390","volume":"26","author":[{"given":"Beatriz","family":"Gil","sequence":"first","affiliation":[{"name":"School of Biomolecular and Biomedical Sciences, University College Dublin, Conway Institute, Dublin 4, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mair\u00e9ad","family":"Sullivan","sequence":"additional","affiliation":[{"name":"School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Conway Institute, Dublin 4, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7463-0676","authenticated-orcid":false,"given":"Caitriona","family":"Scaife","sequence":"additional","affiliation":[{"name":"Conway Institute, University College, Dublin 4, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2371-0422","authenticated-orcid":false,"given":"Jeffrey C.","family":"Glennon","sequence":"additional","affiliation":[{"name":"School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Conway Institute, Dublin 4, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Herron","sequence":"additional","affiliation":[{"name":"School of Biomolecular and Biomedical Sciences, University College Dublin, Conway Institute, Dublin 4, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1073\/pnas.050004797","article-title":"Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer\u2019s disease","volume":"97","author":"Holtzman","year":"2000","journal-title":"Proc. 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