{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T12:05:35Z","timestamp":1773403535527,"version":"3.50.1"},"reference-count":91,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"national funds through FCT\u2014Foundation for Science and Technology, I.P.","award":["2023.13319.PEX"],"award-info":[{"award-number":["2023.13319.PEX"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Amyloid-\u03b2 peptides (A\u03b2) are considered a main culprit of Alzheimer\u2019s disease (AD), leading to synaptic dysfunction and memory deficits. Although studies in animal models of AD converge to show alterations of synaptic plasticity, namely of long-term potentiation (LTP), the mechanisms through which A\u03b2 affects synaptic function remain to be unveiled. In this study, we established experimental conditions showing that the acute exposure of mouse hippocampal slices to optimized concentrations of A\u03b2 impaired short-term (PPF-paired-pulse facilitation) and long-term (LTP-long-term potentiation) plasticity without altering basal synaptic transmission. We observed that the elimination of extracellular adenosine with adenosine deaminase abrogated the impact of A\u03b2 on synaptic plasticity, showing a mandatory involvement of extracellular adenosine in the neurophysiological effects of A\u03b2. Additionally, inhibiting adenosine receptor function with caffeine, as well as selectively blocking adenosine A1 receptors (A1R) with DPCPX, or adenosine A2A receptor (A2AR) with either an antagonist SCH58261 or through knocking out A2AR, demonstrated that acute A\u03b2 modified mouse hippocampal PPF via A1R and LTP through A2AR. Furthermore, the use of slices from mice bearing forebrain-neuron A2AR deletion, along with the application of \u03b1,\u03b2-methylene ADP, a CD73 inhibitor, confirmed that the neurophysiological actions of A\u03b2 on hippocampal LTP occur selectively through the overfunction of neuronal A2AR via CD73-mediated formation of extracellular adenosine. Overall, the exploitation of a neurophysiological model of early AD, based on the acute administration of A\u03b2 to hippocampal slices, confirmed the critical involvement of adenosine signaling in the impact of A\u03b2 on synaptic plasticity.<\/jats:p>","DOI":"10.3390\/cells15060510","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:26:38Z","timestamp":1773393998000},"page":"510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurophysiological In Vitro Model of Amyloid-\u03b2-Induced Deficits of Hippocampal LTP Involving Neuronal Adenosine A2A Receptor Dysfunction Through CD73"],"prefix":"10.3390","volume":"15","author":[{"given":"Francisco Q.","family":"Gon\u00e7alves","sequence":"first","affiliation":[{"name":"Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-3411","authenticated-orcid":false,"given":"Henrique B.","family":"Silva","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8671-989X","authenticated-orcid":false,"given":"\u00c2ngelo R.","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-517 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5523-4945","authenticated-orcid":false,"given":"Paula","family":"Agostinho","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-6422","authenticated-orcid":false,"given":"Rodrigo A.","family":"Cunha","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5122-1802","authenticated-orcid":false,"given":"Jo\u00e3o P.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","article-title":"Amyloid plaque core protein in Alzheimer disease and Down syndrome","volume":"82","author":"Masters","year":"1985","journal-title":"Proc. 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