Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies

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.Abbreviations: 3xTg-AD: triple transgenic AD mice; AD: Alzheimer disease; CSA: cyclosporine A; DBS: deep brain stimulation; DIV: days in vitro; EC: entorhinal cortex; FTD: frontotemporal dementia; gLTP: glycine-induced long-term potentiation; GPi: internal segment of the globus pallidus; PD: Parkinson disease; STN: subthalamic nucleus; TFEB: transcription factor EB

突触是阿尔茨海默病（Alzheimer disease, AD）的重要作用靶标，其兴奋性异常是AD发病进程中最早出现的病理改变之一。已有研究证实，突触激活在AD模型中可发挥神经保护作用；而深部脑刺激（deep brain stimulation, DBS）作为一种通过调控神经元活动以治疗神经及精神疾病的外科策略，在AD患者中已展现出积极疗效。然而，脑刺激发挥保护作用的分子机制至今仍不明确。本课题组此前已证实，通过增强巨自噬（macroautophagy，又称自噬）流及病理性微管相关蛋白Tau（MAPT/Tau）的溶酶体降解，诱导突触活动可在AD及额颞叶痴呆（frontotemporal dementia, FTD）小鼠模型中产生神经保护效应。本研究现已证实，作为溶酶体生物发生与自噬的核心调控因子，转录因子EB（transcription factor EB, TFEB）是该细胞应答的关键介导分子。在FTD转基因小鼠的原代培养神经元中，突触刺激可抑制雷帕霉素靶蛋白复合物1（MTORC1）信号通路，进而促进TFEB的核转位，最终诱导MAPT/Tau寡聚体的清除。反之，在表达组成型激活型RRAG GTP酶（该酶可将TFEB滞留于胞浆内）的神经元中，或在TFEB敲低的神经元中，突触激活无法促进毒性MAPT/Tau的清除。在接受DBS刺激的AD小鼠体内，TFEB的激活效应也得到了体内实验验证。本研究还证实，DBS可降低伴tau蛋白病的帕金森病（Parkinson disease, PD）患者体内的病理性MAPT/Tau水平，并发挥神经保护作用。综上，本研究结果表明，突触活动刺激可通过TFEB介导的通路促进病理性MAPT/Tau的清除。这一作为DBS保护作用核心的分子机制，为将突触刺激应用于tau蛋白病的临床治疗提供了极具前景的理论支撑。

缩略词说明：
3xTg-AD：三转基因AD小鼠
AD：阿尔茨海默病
CSA：环孢素A
DBS：深部脑刺激
DIV：体外培养天数
EC：内嗅皮层
FTD：额颞叶痴呆
gLTP：甘氨酸诱导长时程增强
GPi：苍白球内侧部
PD：帕金森病
STN：丘脑底核
TFEB：转录因子EB