The Role of Synaptic Proteolysis in Alzheimer's Disease and Therapeutic Implications

包含tau的神经元包涵体是阿尔茨海默病(AD)的一个显著特征，额叶 痴呆症(FTD)和其他肌张力障碍，意味着细胞清除错误折叠的tau的能力存在缺陷 作为疾病过程的原因或结果的物种。牛磺酸是泛素的底物 蛋白酶体系统(UPS)，从而阐明蛋白酶体在肌萎缩侧索硬化症中功能失调的机制 可以确定可以作为治疗靶点的途径。突触功能障碍，被认为是一种 阿尔茨海默病和其他疾病的早期病理表现与异常分类错误和 Tau在突触中的积聚。最近的证据表明，阿尔茨海默病突触的致病进展 与突触部分泛素化蛋白的积聚有关，提示UPS功能障碍。 在这里，我们认为突触中错误排列的tau会扰乱蛋白酶体的活动，从而导致更广泛的突触 毒性。我们假设tau诱导的突触蛋白分解受损的后果之一是持续的。 PKA全酶四聚体构象和CREB转录信号下调 与突触可塑性和记忆有关的重要途径。 AIM 1的目标是检查病理性tau在Pre-1中的积聚是否与 突触后区、突触蛋白分解功能及PKA/CREB信号转导状态 使用AD、FTD和正常脑组织。大脑皮层tau物种突触分布的观察 突触前后区及其播种和繁殖的能力将使我们能够识别 突触tau在两种tau病中的生化特征。为了努力找出有助于 突触毒性，AIM 2将使用原代神经元和基于微流控的细胞进行一系列体外测试 流体隔离突触的模型，无论tau聚集体是在整个细胞还是在突触中积累 (在跨突触传播过程中)，可由于受损而对PKA/CREB信号转导产生负面影响 蛋白酶体清除机制。作为一种治疗策略，AIM 3将研究Gs偶联刺激是否 位于突触终末的GPCR拯救/激活cAMP/PKA通路，导致 突触中tau物种的蛋白酶体蛋白分解。受体治疗策略的应用-- 受刺激的蛋白分解具有空间定义的有效清除tau的作用机制，可以识别新的 阻止tau错误分类和随后的跨突触扩散的机制。将GPCR信号作为一种 激活蛋白酶体介导的蛋白分解的策略在寻找新的治疗药物方面具有重要影响 蛋白质病疾病。

Tau-containing neuronal inclusions are a prominent feature of Alzheimer’s disease (AD), frontal temporal dementia (FTD) and other disorders with tauopathy, implying a deficit in the cell’s ability to clear misfolded tau species either as a cause or a consequence of the disease process. Tau is a substrate of the ubiquitin proteasome system (UPS), thus elucidating mechanisms how proteasome becomes dysfunctional in tauopathy may identify pathways that could be targeted therapeutically. Synaptic dysfunction, which is thought to be an early pathological manifestation in AD and other tauopathies, is associated with abnormal missorting and accumulation of tau in synapses. And recent evidence suggests that pathogenic progression in synapses in AD correlates with accumulation of ubiquitinated proteins in synaptic fractions, suggesting UPS dysfunction. Here we propose that missorted tau in synapses disrupts proteasomal activity contributing to broader synaptic toxicity. We hypothesize that one of the consequences of tau-induced impaired synaptic proteolysis is sustained tetrameric (inactive) conformation of PKA holoenzyme and downregulation of CREB transcription signaling, an important pathway related to synaptic plasticity and memory. The goal of AIM 1 is to examine whether there is a relationship between accumulation of pathological tau in pre and post -synaptic compartments, the function of synaptic proteolysis and the status of PKA/CREB signaling using brain tissue from AD, FTD and normal brains. Examination of the synaptic distribution of tau species in the pre and post synaptic compartment and its competency to seed and propagate will enable us to identify the biochemical signature of synaptic tau in two tauopathies. In an effort to identify mechanisms that contribute to synaptic toxicity, AIM 2 will test in a series of in vitro assays using primary neurons and microfluidic-based cell model of fluidically isolated synapses, whether accumulation of tau aggregates throughout the cell or in synapses (during trans-synaptic propagation), can elicit a negative effect on the PKA/CREB signaling due to impaired proteasome clearance mechanism. As a therapeutic strategy, AIM 3 will investigate if stimulation of Gs-coupled GPCR, situated on the synaptic terminals, rescues/activates cAMP/PKA pathway leading to increased proteasome proteolysis of tau species in synapses. The application of a therapeutic strategy of receptor- stimulated proteolysis with spatially defined mechanism of action for effective tau clearance, can identify a new mechanism to halt missorting of tau and subsequent trans-synaptic spread. Targeting GPCR signaling as a strategy to activate proteasome mediated proteolysis can have a significant impact in finding new drugs for proteinopathy diseases.