Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies
Year: 2022
Type: article
Abstract: 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.
Source: Autophagy
Authors: 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
Institutions: Inserm, Université Paris-Saclay, Maladies et hormones du système nerveux, Federico II University Hospital, Telethon Institute Of Genetics And Medicine, University of Naples Federico II, University of the Basque Country, Biomedical Research Networking Center on Neurodegenerative Diseases, Achucarro Basque Center for Neuroscience, University Health Network, Toronto Western Hospital, Krembil Research Institute, Institut Professeur Baulieu, Tecnalia, University of Genoa, Rush University Medical Center, Arizona State University, University of Toronto, Ikerbasque, University of Milan
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4286587481