{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:03:25Z","timestamp":1780401805860,"version":"3.54.1"},"reference-count":81,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"TELETHON","award":["No. 33173212"],"award-info":[{"award-number":["No. 33173212"]}]},{"name":"Cyprus Institute of Neurology and Genetics","award":["No. 33173212"],"award-info":[{"award-number":["No. 33173212"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer\u2019s disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with A\u03b2 plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant A\u03b2 plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding A\u03b2 plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47\u2013Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in Cx32 mRNA levels. Finally, myelin deficits were found focally in the areas occupied by A\u03b2 plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte\u2013astrocyte (O\/A) GJ connectivity is warranted.<\/jats:p>","DOI":"10.3390\/ijms232415597","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T03:23:49Z","timestamp":1670556229000},"page":"15597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6985-0906","authenticated-orcid":false,"given":"Maria","family":"Pechlivanidou","sequence":"first","affiliation":[{"name":"Neurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7491-5946","authenticated-orcid":false,"given":"Ioanna","family":"Kousiappa","sequence":"additional","affiliation":[{"name":"Neurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Angeli","sequence":"additional","affiliation":[{"name":"Medical School, University of Nicosia, Nicosia 2414, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5143-0823","authenticated-orcid":false,"given":"Irene","family":"Sargiannidou","sequence":"additional","affiliation":[{"name":"Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0737-2347","authenticated-orcid":false,"given":"Andreas M.","family":"Koupparis","sequence":"additional","affiliation":[{"name":"Neurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Epilepsy Centre, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Dementia and Cognitive Disorders Centre, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savvas S.","family":"Papacostas","sequence":"additional","affiliation":[{"name":"Neurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Medical School, University of Nicosia, Nicosia 2414, Cyprus"},{"name":"Epilepsy Centre, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Dementia and Cognitive Disorders Centre, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kleopas A.","family":"Kleopa","sequence":"additional","affiliation":[{"name":"Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Center for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Center for Multiple Sclerosis and Related Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1515\/REVNEURO.2010.21.5.397","article-title":"Gap Junction Disorders of Myelinating Cells","volume":"21","author":"Kleopa","year":"2010","journal-title":"Rev. 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