Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies

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dc.contributor.authorAkwa, Yvette
dc.contributor.authorDi Malta, Chiara
dc.contributor.authorZallo, Fátima
dc.contributor.authorGondard, Elise
dc.contributor.authorLunati, Adele
dc.contributor.authorDiaz-de-Grenu, Lara Z.
dc.contributor.authorZampelli, Angela
dc.contributor.authorBoiret, Anne
dc.contributor.authorSantamaria, Sara
dc.contributor.authorMartinez-Preciado, Maialen
dc.contributor.authorCortese, Katia
dc.contributor.authorKordower, Jeffrey H.
dc.contributor.authorMatute, Carlos
dc.contributor.authorLozano, Andres M.
dc.contributor.authorCapetillo-Zarate, Estibaliz
dc.contributor.authorVaccari, Thomas
dc.contributor.authorSettembre, Carmine
dc.contributor.authorBaulieu, Etienne E.
dc.contributor.authorTampellini, Davide
dc.date.accessioned2022-07-29T10:03:27Z
dc.date.available2022-07-29T10:03:27Z
dc.date.issued2022
dc.description.abstractSynapses represent an important target of Alzheimer disease (AD), and alterations of their excitability are among the earliest changes associated with AD development. Synaptic activation has been shown to be protective in models of AD, and deep brain stimulation (DBS), a surgical strategy that modulates neuronal activity to treat neurological and psychiatric disorders, produced positive effects in AD patients. However, the molecular mechanisms underlying the protective role(s) of brain stimulation are still elusive. We have previously demonstrated that induction of synaptic activity exerts protection in mouse models of AD and frontotemporal dementia (FTD) by enhancing the macroautophagy/autophagy flux and lysosomal degradation of pathological MAPT/Tau. We now provide evidence that TFEB (transcription factor EB), a master regulator of lysosomal biogenesis and autophagy, is a key mediator of this cellular response. In cultured primary neurons from FTD-transgenic mice, synaptic stimulation inhibits MTORC1 signaling, thus promoting nuclear translocation of TFEB, which, in turn, induces clearance of MAPT/Tau oligomers. Conversely, synaptic activation fails to promote clearance of toxic MAPT/Tau in neurons expressing constitutively active RRAG GTPases, which sequester TFEB in the cytosol, or upon TFEB depletion. Activation of TFEB is also confirmed in vivo in DBS-stimulated AD mice. We also demonstrate that DBS reduces pathological MAPT/Tau and promotes neuroprotection in Parkinson disease patients with tauopathy. Altogether our findings indicate that stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau. This mechanism, underlying the protective effect of DBS, provides encouraging support for the use of synaptic stimulation as a therapeutic treatment against tauopathies.en
dc.description.sponsorshipThis work was supported by the ELKARTEK [KK-2020/00034]; Spanish Ministry of Science and Innovation [PID2019-109724RB-I00]; CIBERNED [CB06/0005/0076]; T.V. is supported by AIRC, IG 2017 #20661, and Italian Ministery of University and Research grant [PRIN2020CLZ5XWTV].en
dc.identifier.citationYvette Akwa, Chiara Di Malta, Fátima Zallo, Elise Gondard, Adele Lunati, Lara Z. Diaz-de-Grenu, Angela Zampelli, Anne Boiret, Sara Santamaria, Maialen Martinez-Preciado, Katia Cortese, Jeffrey H. Kordower, Carlos Matute, Andres M. Lozano, Estibaliz Capetillo-Zarate, Thomas Vaccari, Carmine Settembre, Etienne E. Baulieu & Davide Tampellini (2022): Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies, Autophagy, DOI: 10.1080/15548627.2022.2095791en
dc.identifier.doi10.1080/15548627.2022.2095791en
dc.identifier.essn1554-8635en
dc.identifier.issn1554-8627en
dc.identifier.urihttp://hdl.handle.net/11556/1389
dc.journal.titleAutophagyen
dc.language.isoengen
dc.page.final18en
dc.page.initial1en
dc.publisherTaylor and Francis Ltd.en
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.accessRightsopen accessen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.keywordsAlzheimeren
dc.subject.keywordsAutophagyen
dc.subject.keywordsDeep brain stimulationen
dc.subject.keywordsLysosomeen
dc.subject.keywordsNeuronen
dc.subject.keywordsSynapseen
dc.subject.keywordsTauen
dc.titleStimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathiesen
dc.typejournal articleen
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