Mechanisms of TDP-43 neurotoxicity in Alzheimer's disease

阿尔茨海默氏病，一种严重的进行性神经退行性疾病的老化和最常见的形式 痴呆症，影响了全球约3000万人。从病理学上讲，老年痴呆症是 由淀粉样蛋白-β（Aβ）和神经胶质细胞组成的淀粉样斑块的存在定义。 疾病影响的大脑区域中含有tau蛋白的缠结。然而，超过一半的老年痴呆症 疾病患者还表现出TDP-43聚集体作为另外的共同病理。TDP-43的存在 阿尔茨海默病的病理学与海马硬化、更严重的脑萎缩、更严重的 认知障碍和更快的认知能力下降。鉴于最近承认TDP-43是一种 阿尔茨海默病中常见的共同病理学，了解其对神经退行性疾病的贡献 过程和与其他病理性疾病促进蛋白质的潜在协同作用是一个关键的需要， 外地最近的工作使用C。elegans发现，共表达tau和TDP-43导致增加的 神经毒性和病理性蛋白质积累。在此基础上，拟议的目标将 开发和利用共表达tau和TDP-43的新模型，以了解生物学 潜在的协同毒性。目的1将定义tau亚型和TDP-43蛋白结构域的要求 使用精确的基因编辑，结合敏感的行为和 神经影像学检测C.优雅目标2将使用tau和TDP-43共表达的新小鼠模型， 通过衰老绘制神经元脆弱性、病理性蛋白质积累和神经退行性变， 哺乳动物的大脑我们还将使用以下方法确定对共病tau和TDP-43的细胞特异性应答： 空间转录组学这项工作将表征tau和TDP-43神经毒性的潜在机制， 阿尔茨海默病和确定新的治疗目标和策略。该项目的完成将 显著推进了对阿尔茨海默病与TDP-43共病的理解，并提供了 为将来针对TDP-43的阿尔茨海默病治疗开发奠定基础。

Alzheimer's disease, a severe progressive neurodegenerative disease of aging and the most common form of dementia, affects an estimated 30 million people worldwide. Pathologically, Alzheimer's disease is defined by the presence of both amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau in disease affected brain regions. However, more than half of Alzheimer's disease patients also exhibit TDP-43 aggregates as an additional co-pathology. The presence of TDP-43 pathology in Alzheimer's disease correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. Given the recent recognition of TDP-43 as a frequent co-pathology in Alzheimer's disease, understanding its contribution to neurodegenerative disease processes and potential synergies with other pathological disease-promoting proteins is a critical need in the field. Recent work using C. elegans found that co-expressed tau and TDP-43 leads to increased neurotoxicity and pathological protein accumulation. Building on this foundation, the proposed Aims will develop and utilize new models of co-expressed tau and TDP-43 in order to understand the biology underlying their synergistic toxicity. Aim 1 will define tau isoform and TDP-43 protein domain requirements for enhanced neurotoxicity using precision gene editing, combined with sensitive behavioral and neuroimaging assays in C. elegans. Aim 2 will use a new mouse model of tau and TDP-43 co-expression to map neuronal vulnerabilities, pathological protein accumulation, and neurodegeneration through aging in the mammalian brain. We will also determine cell specific responses to co-morbid tau and TDP-43 using spatial transcriptomics. This work will characterize mechanisms underlying tau and TDP-43 neurotoxicity in Alzheimer's disease and identify new therapeutic targets and strategies. Completion of this project will significantly advance understanding of Alzheimer's disease with comorbid TDP-43, and provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer's disease.