TDP-43 in Alzheimer's disease

阿尔茨海默病，一种严重的进行性神经退行性疾病，是最常见的 痴呆症，全球估计有3000万人患有痴呆症。从病理学上讲，阿尔茨海默病的定义是 由淀粉样蛋白β(Aβ)和神经原纤维缠结组成的淀粉样斑块的存在 在疾病影响的大脑区域中含有tau蛋白。然而，30%-57%的阿尔茨海默病患者 还展示了TDP-43聚集物作为另一种共同病理。TDP-43基因在卵巢癌中的表达 阿尔茨海默病与海马区硬化、更严重的脑萎缩、更严重的认知 损伤，以及更快的认知能力下降。鉴于最近认识到TDP-43是一种频繁的联合- 阿尔茨海默病的病理学，了解其在神经退行性疾病过程中的作用和 与其他病理疾病促进蛋白的潜在协同作用是该领域的关键需求。近期 使用线虫的研究发现，共表达tau和TDP-43会导致神经毒性增加和 病理性蛋白质堆积。在此基础上，拟议的目标将开发和利用新的 共表达tau和TDP-43的易处理模型，以了解其毒性的生物学基础。 目标1将定义低水平或可调节的共表达tau和TDP-43的后果 和神经成像分析，并测试tau和TDP-43之间的关系。AIMS 2和3将使用RNA 测序以揭示在简单模型中伴随的tau和TDP-43通过衰老的基因表达， 以及人类死后脑组织中的TDP-43病理阿尔茨海默病患者。 从转录切除法提名的候选人将接受tau和tdp-43的功能测试。 使用遗传和转基因方法的协同性蛋白质病。这项工作将描述机构的特征 在阿尔茨海默病中潜在的tau和TDP-43神经毒性并确定新的治疗靶点和 战略。该项目的完成将极大地促进对阿尔茨海默病的了解 为将来靶向TDP-43的治疗研究奠定了基础。 阿尔茨海默氏症。

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, 30-57% 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 tractable models of co-expressed tau and TDP-43 in order to understand the biology underlying their toxicity. Aim 1 will define consequences of low or regulatable levels of co-expressed tau and TDP-43 using behavioral and neuroimaging assays, and test relationships between tau and TDP-43. Aims 2 and 3 will employ RNA sequencing to reveal gene expression underlying comorbid tau and TDP-43 through aging in simple models, and in human post-mortem brain tissue from patients with Alzheimer’s disease with TDP-43 pathology. Candidates nominated from transcriptomic approaches will be tested for functional roles in tau and TDP-43 synergistic proteinopathy using genetic and transgenic approaches. 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 Alzheimer’s disease with comorbid TDP-43, and provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer’s disease.