Tau-mediated synaptic dysfunction in age-related neurodegenerative diseases

微管相关蛋白tau的神经原纤维缠结(NFT)是大脑老化的普遍特征。 Tau病理在整个大脑中的程度与突触丢失和认知严重程度相关。 年龄相关性肌萎缩侧索硬化症的损害。通过大脑积累NFT来维持认知功能的能力 依赖于突触网络的保存和维护。因此，通过以下方式理解这一机制 哪些tau参与了网络和突触的脆弱性，这对开发预防性治疗方法至关重要。 这项提议的目标是确定病理性tau驱动神经元的细胞机制(S)。 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 为顺利过渡到博士后职位提供智力和技术培训。F99阶段(目标1) 将测试机械细胞生物学假说，以更好地定义tau异常积累如何诱导突触 功能障碍，同时提供机会发展错综复杂的实验设计和执行技能 尖端生物化学、显微镜和电生理学技术。K00阶段(目标2)将建立在 F99研究使用计算策略来整合来自人类和实验的蛋白质组学数据 识别与年龄相关的肌萎缩侧索硬化症高度相关的共存分子变化的模型。

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.