RT Journal Article
T1 Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies
A1 Akwa, Yvette
A1 Di Malta, Chiara
A1 Zallo, Fátima
A1 Gondard, Elise
A1 Lunati, Adele
A1 Diaz-de-Grenu, Lara Z.
A1 Zampelli, Angela
A1 Boiret, Anne
A1 Santamaria, Sara
A1 Martinez-Preciado, Maialen
A1 Cortese, Katia
A1 Kordower, Jeffrey H.
A1 Matute, Carlos
A1 Lozano, Andres M.
A1 Capetillo-Zarate, Estibaliz
A1 Vaccari, Thomas
A1 Settembre, Carmine
A1 Baulieu, Etienne E.
A1 Tampellini, Davide
AB Synapses 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.
PB Taylor and Francis Ltd.
SN 1554-8627
YR 2022
FD 2022
LK http://hdl.handle.net/11556/1389
UL http://hdl.handle.net/11556/1389
LA eng
NO Yvette 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: 10.1080/15548627.2022.2095791
NO This 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].
DS TECNALIA Publications
RD 3 jul 2024