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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.

Evidence suggests that lightly myelinated cortical regions are vulnerable to aging and Alzheimer's disease (AD). However, it remains unknown whether plasma markers of amyloid and neurodegeneration are related to deficits in intracortical myelin content, and whether this relationship, in turn, is associated with altered patterns of resting-state functional connectivity (rs-FC). To shed light into these questions, plasma levels of amyloid-beta fragment 1-42 (A beta(1-42)) and neurofilament light chain (NfL) were measured using ultra-sensitive single-molecule array (Simoa) assays, and the intracortical myelin content was estimated with the ratio T1-weigthed/T2-weighted (T1w/T2w) in 133 cognitively normal older adults. We assessed: (i) whether plasma A beta(1-42) and/or NfL levels were associated with intracortical myelin content at different cortical depths and (ii) whether cortical regions showing myelin reductions also exhibited altered rs-FC patterns. Surface-based multiple regression analyses revealed that lower plasma A beta(1-42) and higher plasma NfL were associated with lower myelin content in temporo-parietal-occipital regions and the insular cortex, respectively. Whereas the association with A beta(1-42) decreased with depth, the NfL-myelin relationship was most evident in the innermost layer. Older individuals with higher plasma NfL levels also exhibited altered rs-FC between the insula and medial orbitofrontal cortex. Together, these findings establish a link between plasma markers of amyloid/neurodegeneration and intracortical myelin content in cognitively normal older adults, and support the role of plasma NfL in boosting aberrant FC patterns of the insular cortex, a central brain hub highly vulnerable to aging and neurodegeneration.