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In Huntington\u2019s disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3<jats:italic>\u03b2<\/jats:italic>expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2\u20134) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry.<jats:italic>In vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>studies looking at hippocampal pathology and GSK-3<jats:italic>\u03b2<\/jats:italic>were also undertaken in transgenic R6\/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3<jats:italic>\u03b2<\/jats:italic>mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3<jats:italic>\u03b2<\/jats:italic>-Tyr<jats:sup>216<\/jats:sup>being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3<jats:italic>\u03b2<\/jats:italic>-Tyr<jats:sup>216<\/jats:sup>was also found in the R6\/2 hippocampus<jats:italic>in vivo<\/jats:italic>and linked to the increased vulnerability of primary hippocampal neurons<jats:italic>in vitro<\/jats:italic>. In addition, the increased expression of GSK-3<jats:italic>\u03b2<\/jats:italic>in the astrocytes of R6\/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3<jats:italic>\u03b2<\/jats:italic>in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3<jats:italic>\u03b2<\/jats:italic>as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD.<\/jats:p>","DOI":"10.1038\/cddis.2016.104","type":"journal-article","created":{"date-parts":[[2016,4,28]],"date-time":"2016-04-28T12:50:35Z","timestamp":1461847835000},"page":"e2206-e2206","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["GSK-3\u03b2-induced Tau pathology drives hippocampal neuronal cell death in Huntington\u2019s disease: involvement of astrocyte\u2013neuron interactions"],"prefix":"10.1038","volume":"7","author":[{"given":"F","family":"L'Episcopo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Drouin-Ouellet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Tirolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Pulvirenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Giugno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Testa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Caniglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M F","family":"Serapide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Cisbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R A","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Cicchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9287-8448","authenticated-orcid":false,"given":"B","family":"Marchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,28]]},"reference":[{"key":"BFcddis2016104_CR1","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1097\/00005072-199805000-00001","volume":"57","author":"JP Vonsattel","year":"1998","unstructured":"Vonsattel JP, DiFiglia M . 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