Mitochondrial TDP-43 in Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是老年痴呆的主要原因，其特征在于神经元缠结， 老年斑以及新皮层和海马中神经元细胞的进行性损失。目前尚无 有效治疗AD。TAR DNA结合蛋白43（TDP-43）基因突变导致肌萎缩侧索硬化症 硬化症（ALS）和额颞叶痴呆（FTD，早发性痴呆的第二种最常见形式）， TDP-43在细胞质中的增加是退行性变的显著组织病理学特征， 超过一半的AD患者的神经元。尽管越来越多的证据表明TDP-43可能是 除了淀粉样蛋白外，“第三种蛋白”在AD或相关痴呆的发病机制中发挥独特作用 尽管TDP-43的分子病理机制与Aβ和tau蛋白的表达密切相关，但TDP-43的分子病理机制仍然难以捉摸。有趣的是，在我们的初步研究中， 在研究中，我们发现TDP-43与AD患者的线粒体高度相关， Aβ和APP/PS1（5XFAD）转基因小鼠AD。基于对TDP-43线粒体的关键识别的基序 定位，我们最近的研究表明，TDP-43线粒体定位的抑制， 足以防止TDP-43诱导的神经元损失，并改善TDP-43转基因小鼠的行为表现。 小鼠，表明线粒体作为TDP-43神经毒性的重要介质。令人兴奋的是，抑制TDP- 43线粒体定位可显著减轻5XFAD小鼠的神经元死亡和行为缺陷 在症状发作后很长时间。这些令人兴奋和有希望的初步研究表明， 研究阿尔茨海默病相关TDP-43在AD和相关痴呆中的潜在作用是必要的。同时使用 本研究将测试AD和相关痴呆的培养神经元和转基因小鼠模型的可行性 靶向阿尔茨海默病相关TDP-43作为AD和相关痴呆症的新治疗方法。的 TDP-43在细胞质中的增加是一个突出的共同组织病理学特征， 在包括AD、FTD和ALS的各种主要神经退行性疾病中的退化神经元。我们提出的 对阿尔茨海默病相关的TDP-43及其与普遍认为的AD罪魁祸首Aβ的联系的研究将使 非常广泛的科学和翻译意义。

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.