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Wolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice

dc.rights.licenseopenen_US
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorDELPECH, Jean-Christophe
dc.contributor.authorPATHAK, Dhruba
dc.contributor.authorVARGHESE, Merina
dc.contributor.authorKALAVAI, Srinidhi Venkatesan
dc.contributor.authorHAYS, Emma C.
dc.contributor.authorHOF, Patrick R.
dc.contributor.authorJOHNSON, W. Evan
dc.contributor.authorIKEZU, Seiko
dc.contributor.authorMEDALLA, Maria
dc.contributor.authorLUEBKE, Jennifer
dc.contributor.authorIKEZU, Tsuneya
dc.date.accessioned2021-10-19T14:26:52Z
dc.date.available2021-10-19T14:26:52Z
dc.date.issued2021-09-15
dc.identifier.issn1946-6234en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/112814
dc.description.abstractEnAbnormally phosphorylated tau, an early neuropathologic marker of Alzheimer’s disease (AD), first occurs in the brain’s entorhinal cortex layer II (ECII) and then spreads to the CA1 field of the hippocampus. Animal models of tau propagation aiming to recapitulate this phenomenon mostly show tau transfer from ECII stellate neurons to the dentate gyrus, but tau pathology in the dentate gyrus does not appear until advanced stages of AD. Wolframin-1–expressing (Wfs1+) pyramidal neurons have been shown functionally to modulate hippocampal CA1 neurons in mice. Here, we report that Wfs1+ pyramidal neurons are conserved in the ECII of postmortem human brain tissue and that Wfs1 colocalized with abnormally phosphorylated tau in brains from individuals with early AD. Wfs1+ neuron–specific expression of human P301L mutant tau in mouse ECII resulted in transfer of tau to hippocampal CA1 pyramidal neurons, suggesting spread of tau pathology as observed in the early Braak stages of AD. In mice expressing human mutant tau specifically in the ECII brain region, electrophysiological recordings of CA1 pyramidal neurons showed reduced excitability. Multielectrode array recordings of optogenetically stimulated Wfs1+ ECII axons resulted in reduced CA1 neuronal firing. Chemogenetic activation of CA1 pyramidal neurons showed a reduction in c-fos+ cells in the CA1. Last, a fear conditioning task revealed deficits in trace and contextual memory in mice overexpressing human mutant tau in the ECII. This work demonstrates tau transfer from the ECII to CA1 in mouse brain and provides an early Braak stage preclinical model of AD.
dc.language.isoENen_US
dc.title.enWolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice
dc.typeArticle de revueen_US
dc.identifier.doi10.1126/scitranslmed.abe8455en_US
dc.subject.halSciences du Vivant [q-bio]/Neurosciences [q-bio.NC]en_US
dc.identifier.pubmed34524859en_US
bordeaux.journalScience Translational Medicineen_US
bordeaux.volume13en_US
bordeaux.hal.laboratoriesNutriNeurO (Laboratoire de Nutrition et Neurobiologie Intégrée) - UMR 1286en_US
bordeaux.issue611en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINRAEen_US
bordeaux.teamPsychoneuroimmunologie et Nutrition: Approches expérimentales et cliniquesen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03385929
hal.version1
hal.date.transferred2021-10-19T14:27:50Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Science%20Translational%20Medicine&rft.date=2021-09-15&rft.volume=13&rft.issue=611&rft.eissn=1946-6234&rft.issn=1946-6234&rft.au=DELPECH,%20Jean-Christophe&PATHAK,%20Dhruba&VARGHESE,%20Merina&KALAVAI,%20Srinidhi%20Venkatesan&HAYS,%20Emma%20C.&rft.genre=article


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