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

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.contributor.institutionTecnalia Research & Innovation
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.statusPeer reviewed
dc.format.extent18
dc.format.extent5189253
dc.identifier.citationAkwa , Y , Di Malta , C , Zallo , F , Gondard , E , Lunati , A , Diaz-de-Grenu , L Z , Zampelli , A , Boiret , A , Santamaria , S , Martinez-Preciado , M , Cortese , K , Kordower , J H , Matute , C , Lozano , A M , Capetillo-Zarate , E , Vaccari , T , Settembre , C , Baulieu , E E & Tampellini , D 2022 , ' Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies ' , Autophagy , vol. unknown , pp. 1-18 . https://doi.org/10.1080/15548627.2022.2095791
dc.identifier.doi10.1080/15548627.2022.2095791
dc.identifier.issn1554-8635
dc.identifier.otherresearchoutputwizard: 11556/1389
dc.language.isoeng
dc.relation.ispartofAutophagy
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subject.keywordsAlzheimer
dc.subject.keywordsAutophagy
dc.subject.keywordsDeep brain stimulation
dc.subject.keywordsLysosome
dc.subject.keywordsNeuron
dc.subject.keywordsSynapse
dc.subject.keywordsTau
dc.subject.keywordsAlzheimer
dc.subject.keywordsAutophagy
dc.subject.keywordsDeep brain stimulation
dc.subject.keywordsLysosome
dc.subject.keywordsNeuron
dc.subject.keywordsSynapse
dc.subject.keywordsTau
dc.subject.keywordsFunding Info
dc.subject.keywordsThis 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].
dc.subject.keywordsThis 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].
dc.titleStimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathiesen
dc.typejournal article
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