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PROTECTIVE EFFECTS OF SYNAPTIC STIMULATION BY PATHOLOGIC TAU CLEARANCE IN AD AND PD
Abstract
Aims
Objectives
Loss of synapses and alterations of synaptic plasticity are central events in Alzheimer’s disease (AD) and Parkinson’s disease (PD) pathogenesis; and they are associated with progressive accumulation of tau protein. Recent studies demonstrated protective effects of neuronal/synaptic activation, via deep brain stimulation (DBS) or other means, in model of AD and PD, including reduction of pathological tau and neuroprotection. We have found that synaptic stimulation enhanced auto-lysosomal degradation of pathologic tau protecting synapses (Akwa et al., 2018).
Currently, we are exploring the cellular mechanism(s) responsible for such positive outcomes. Recently, we have found the involvement of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal proteins, in tau clearance upon stimulation.
Methods
Synaptic activity was induced by electrode implantation in the entorhinal cortex of 3xTg mice, or chemically in primary neurons prepared from tau mice PS19. Data of DBS treatment were confirmed in PD patients who underwent DBS. We performed RT-qPCR, live imaging, biochemical and histological analyses and relative statistical analyses.
Results
DBS reduced levels of pathological tau in 3xTg mice. Data were confirmed in DBS-treated PD patients. Tau clearance required lysosmal activity, which was enhanced by DBS. TFEB activation was also trigger by stimulation, and RT-qPCR analyses revealed increased transcription of TFEB downstream genes, including lysosomal ATP6-V1H, ATP6-V0D1, in neurons.
Conclusions
DBS reduces levels of pathologic tau in models of AD and PD brains. In addition, we found that at cellular and molecular level synaptic activity enhances lysosomal degradation and triggers TFEB inducing the transcription of its downstream genes.