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Synaptic stimulation protects against pathological tau by enhancing lysosomal degradation

Changes in synaptic excitability and reduced brain metabolism are among the earliest alterations associated with the development of Alzheimer’s disease (AD) (Reiman et al., 2004; Sperling et al., 2009). Among different approaches for therapeutics, the stimulation of synaptic activity has been shown to be protective in models of AD, and deep brain stimulation (DBS) provides amelioration in AD patients (Sankar et al., 2015; Swaab and Bao, 2010; Tampellini, 2015). Such positive effects might reflect changes occurring at cellular levels when activity is induced, indicating that brain stimulation might promote cellular mechanisms correcting neuronal and synaptic dysfunctions. We have demonstrated that synaptic stimulation, via DBS or other methods, exerts protection in mouse models of AD and frontotemporal dementia (FTD) by enhancing autophagy, lysosomal degradation of pathologic tau, and protecting synapses (Akwa et al., 2018; Mann et al., 2018). Ongoing investigations are revealing the involvement of TFEB and its downstream genes in the enhancement of lysosomal activity upon stimulation.