Synaptic stimulation induces tau clearance by enhancing autophagosomal/lysosomal degradation.

Abstract

Alterations of synaptic excitability and reduced brain metabolism are some of the earliest changes associated Alzheimer's disease (AD) pathogenesis (Reiman et al., 2004; Sperling et al., 2009). Among different approaches for therapeutics, the stimulation of synaptic activity exerts protective effects in models of AD, and deep brain stimulation (DBS) has been shown to ameliorate AD symptoms in certain patients (Sankar et al., 2015; Swaab and Bao, 2010; Tampellini, 2015). Such positive effects might be the result of changes occurring at cellular level upon activity induction, which promote cellular mechanisms correcting neuronal and synaptic dysfunctions. We have demonstrated that synaptic stimulation, via DBS or other methods, is protective in mouse models of AD and frontotemporal dementia (FTD) by enhancing autophagy and lysosomal degradation of pathologic tau, and by protecting synapses (Akwa et al., 2018; Mann et al., 2018). Our more recent investigations are revealing the involvement of Transcription factor EB (TFEB), a pivotal player in lysosomal biogenesis and autophagy (Sardiello et al., 2009), and its downstream genes in the enhancement of lysosomal activity upon stimulation. 3xTg mice received deep brain stimulation by electrode implantation in the entorhinal cortex (Mann et al., 2018). Cultured neurons were prepared from E15 PS19 mouse embryos (Akwa et al., 2018) and stimulated at 14 days in vitro (Ehlers, 2003). Confocal immunofluorescence, Western blot and statistical analyses were performed as described (Akwa et al., 2018). RT-qPCR was performed as described (Napolitano et al., 2018). DBS was able to reduce levels of hyperphosphorylated and oligomeric (but not total) tau restoring levels of synaptic proteins back to wild-type in 3xTg mice. Pathological tau clearance occurred via autophagic pathway and lysosomal activity, the latest being enhanced by synaptic stimulation. TFEB was required for tau clearance as its inhibition prevented activity-induced reduction of pathological tau. In addition, RT-qPCR data analyses revealed increase expressions of TFEB downstream genes, including ATP6-V1H, ATP6-V0D1, and mucolipin-1 in neurons during synaptic stimulation. Protective effects of DBS/synaptic stimulation against pathological tau include the involvement TFEB and the enhancement of autophagy and lysosomal degradation.