Mitochondrial TDP-43 in Alzheimer's Disease

阿尔茨海默病中的线粒体 TDP-43

• 批准号: 10578054
• 负责人: Xinglong Wang
• 金额: $ 115.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2022-10-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578054
• 关键词: Mitochondrial; TDP; 43; Alzheimer; Disease

PROJECT SUMMARY Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in neocortex and hippocampus. Currently, there is no effective treatment for AD. Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD, the second most common form of early-onset dementia), and the increased presence of TDP-43 in the cytoplasm is a prominent histopathological feature of degenerating neurons in more than half of AD patients. Despite an expanding body of evidence suggests that TDP-43 may be “the third protein” playing a distinct role in the pathogenesis of AD or related dementia, in addition to amyloid beta (Aβ) and tau, the molecular pathomechanisms of TDP-43 remain elusive. Interestingly, in our preliminary studies, we found that TDP-43 became highly associated with mitochondria in AD patients, neurons treated with Aβ and APP/PS1 (5XFAD) transgenic mice for AD. Based on identified motifs critical for TDP-43 mitochondrial localization, our most recent study revealed that the suppression of TDP-43 mitochondrial localization was sufficient to prevent TDP-43-induced neuronal loss, and improve behavioral performances in TDP-43 transgenic mice, indicating mitochondria as important mediators for TDP-43 neurotoxicity. Excitingly, the inhibition of TDP-43 mitochondrial localization could significantly alleviate neuronal death and behavioral deficits in 5XFAD mice well after symptom onset. These exciting and promising preliminary studies suggest that a detailed investigation into the potential role of mitochondria- associated TDP-43 in AD and related dementia is warranted. Using both cultured neuronal and transgenic mouse models for AD and related dementia, this study will test the feasibility of targeting mitochondria- associated TDP-43 as a novel therapeutic approach for AD and related dementia. The increased presence of TDP-43 in the cytoplasm is a prominent common histopathological feature of degenerating neurons in various major neurodegenerative diseases including AD, FTD and ALS. Our proposed studies of mitochondria- associated TDP-43 and its connection with the generally believed AD culprit Aβ will have very broad scientific and translational significance.

项目概要 阿尔茨海默病（AD）是老年人痴呆的主要原因，其特征是神经原纤维 缠结、老年斑以及新皮质和海马神经元细胞的逐渐丧失。现在， AD 没有有效的治疗方法。 TAR DNA 结合蛋白 43 (TDP-43) 基因突变导致 肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 是第二种最常见的疾病 早发性痴呆），细胞质中 TDP-43 的增加是一个显着的 超过一半的 AD 患者神经元退化的组织病理学特征。尽管身体不断膨胀 大量证据表明 TDP-43 可能是在 AD 或 AD 的发病机制中发挥独特作用的“第三种蛋白质” 与痴呆相关，除了β淀粉样蛋白（Aβ）和tau蛋白外，TDP-43的分子病理机制仍然存在 难以捉摸。有趣的是，在我们的初步研究中，我们发现 TDP-43 与 AD 患者的线粒体、用 Aβ 治疗的神经元和 APP/PS1 (5XFAD) 转基因小鼠治疗 AD。基于 关于确定的对 TDP-43 线粒体定位至关重要的基序，我们最近的研究表明 抑制 TDP-43 线粒体定位足以防止 TDP-43 诱导的神经元损失，并且 改善 TDP-43 转基因小鼠的行为表现，表明线粒体是重要的介质 TDP-43 神经毒性。令人兴奋的是，抑制 TDP-43 线粒体定位可以显着 缓解 5XFAD 小鼠症状出现后的神经元死亡和行为缺陷。这些激动人心且 有希望的初步研究表明，对线粒体的潜在作用进行详细研究 AD 和相关痴呆症中相关的 TDP-43 是有道理的。同时使用培养的神经元和转基因 AD 和相关痴呆症的小鼠模型，这项研究将测试靶向线粒体的可行性 相关的 TDP-43 作为 AD 和相关痴呆症的新型治疗方法。存在的增加 细胞质中的 TDP-43 是各种退化神经元的一个突出的共同组织病理学特征。 主要的神经退行性疾病包括 AD、FTD 和 ALS。我们提出的线粒体研究- 相关的 TDP-43 及其与普遍认为的 AD 罪魁祸首 Aβ 的联系将具有非常广泛的科学依据 和翻译意义。