title: GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte-neuron interactions.
abstract: Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's 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-3β expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2-4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3β were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3β mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3β-Tyr(216) 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-3β-Tyr(216) was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3β 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-3β in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3β 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.
authors.affiliation: Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina (EN), Italy.|Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology and Physiology Sections, University of Catania, Via S. Sofia 64, Catania 95125, Italy.
authors.forename: F
authors.initials: F
authors.lastname: L'Episcopo
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11, Lund S-221 84, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Drouin-Ouellet
authors.affiliation: Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina (EN), Italy.
authors.forename: C
authors.initials: C
authors.lastname: Tirolo
authors.affiliation: Department of Clinical and Experimental Medicine, Mathematics and Computer Science Section, University of Catania, Viale A. Doria, Catania 95125, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pulvirenti
authors.affiliation: Department of Clinical and Experimental Medicine, Mathematics and Computer Science Section, University of Catania, Viale A. Doria, Catania 95125, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Giugno
authors.affiliation: Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina (EN), Italy.
authors.forename: N
authors.initials: N
authors.lastname: Testa
authors.affiliation: Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina (EN), Italy.
authors.forename: S
authors.initials: S
authors.lastname: Caniglia
authors.affiliation: Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology and Physiology Sections, University of Catania, Via S. Sofia 64, Catania 95125, Italy.
authors.forename: M F
authors.initials: MF
authors.lastname: Serapide
authors.affiliation: Centre de Recherche du CHU de Québec (CHUQ), Axe Neuroscience, Québec, QC G1V 4G2, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Cisbani
authors.affiliation: Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11, Lund S-221 84, Sweden.|John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 0PY, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Centre de Recherche du CHU de Québec (CHUQ), Axe Neuroscience, Québec, QC G1V 4G2, Canada.|Département de Psychiatrie and Neurosciences, Université Laval, Québec, QC G1V 0A6, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Cicchetti
authors.affiliation: Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina (EN), Italy.|Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology and Physiology Sections, University of Catania, Via S. Sofia 64, Catania 95125, Italy.
authors.forename: B
authors.identifier: http://orcid.org/0000-0002-9287-8448
authors.initials: B
authors.lastname: Marchetti
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020033:Protein Isoforms; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D053148:Caspase 3