Tau-mediated synaptic dysfunction in age-related neurodegenerative diseases

微管相关蛋白tau的神经元缠结（NFT）是衰老大脑的普遍特征。 整个大脑中tau病理的程度与突触丧失和认知功能障碍的严重程度相关。 与年龄相关的Tau蛋白病的损伤。在大脑积累NFT的情况下维持认知功能的能力 依赖于突触网络的保存和维护。因此，通过以下方式了解该机制 哪种tau导致网络和突触脆弱性对于开发预防性治疗是至关重要的。 本提案的目标是确定病理性tau蛋白驱动神经元凋亡的细胞机制。 网络功能障碍本申请中提出的实验将揭示这些机制，并提供 知识和技术培训，以便成功过渡到博士后职位。F99阶段（目标1） 将测试机制细胞生物学假设，以更好地定义异常tau蛋白积累如何诱导突触 功能障碍，同时提供机会，发展复杂的实验设计和执行技能，通过 尖端的生物化学显微镜和电生理学技术K00阶段（目标2）将建立在 F99研究采用计算策略整合来自人类和实验的蛋白质组学数据， 模型来识别与年龄相关的tau蛋白病高度相关的共存分子变化。

Neurofibrillary tangles (NFTs) of the microtubule-associated protein tau are a universal feature of the aging brain. The extent of tau pathology throughout the brain correlates with both synapse loss and severity of cognitive impairment in age-related tauopathies. The ability to maintain cognitive function with a brain accumulating NFTs relies on the preservation and maintenance of synaptic networks. Therefore, understanding the mechanism by which tau contributes to network and synapse vulnerability is critical for developing preventative therapeutics. The goal of this proposal is to determine the cellular mechanism(s) by which pathologic tau drives neuronal network dysfunction. The experiments proposed in this application will uncover these mechanisms and provide intellectual and technical training for a successful transition into a postdoctoral position. The F99 phase (Aim 1) will test mechanistic cell biological hypotheses to better define how abnormal tau accumulation induces synaptic dysfunction, while providing opportunity to develop intricate experimental design and execution skills through cutting-edge biochemistry, microscopy, and electrophysiology techniques. The K00 phase (Aim 2) will build upon the F99 studies with computational strategies to integrate proteomics data from humans and experimental models to identify co-existing molecular changes that are highly relevant to age-related tauopathies.