Mitochondrial TDP-43 in Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是老年人痴呆的主要原因，以神经原纤维为特征 新皮质和海马区神经元细胞进行性丢失。目前， 目前尚无治疗阿尔茨海默病的有效方法。TDP-43基因突变引起 肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)，第二种最常见的形式 早发性痴呆)，TDP-43在细胞质中的存在增加是一个显著的 半数以上AD患者变性神经元的组织病理学特征。尽管身体在膨胀 大量证据表明，TDP-43可能是在AD发病机制中起重要作用的“第三种蛋白”。 与痴呆相关，除了淀粉样β蛋白(Aβ)和tau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患者线粒体、Aβ处理的神经元和APP/PS1(5XFAD)转基因小鼠的AD。基座 在已确定的对TDP-43线粒体定位至关重要的基序上，我们最新的研究表明， 抑制TDP-43线粒体定位足以防止TDP-43诱导的神经元丢失，以及 改善TDP-43转基因小鼠的行为表现，表明线粒体是重要的介体 用于TDP-43的神经毒性。令人兴奋的是，TDP-43线粒体定位的抑制可以显著 在症状出现后很好地减轻5XFAD小鼠的神经元死亡和行为缺陷。这些令人兴奋的和 有希望的初步研究表明，对线粒体潜在作用的详细研究- 相关的TDP-43在AD和相关痴呆中是有根据的。同时使用培养的神经元和转基因 为了建立AD和相关痴呆的小鼠模型，本研究将测试靶向线粒体的可行性。 相关的TDP-43作为治疗AD和相关痴呆的新方法。越来越多的美国人 胞浆中的TDP-43是各种不同类型退行性神经元的共同组织病理学特征。 主要神经退行性疾病包括AD、FTD和ALS。我们提议的线粒体研究- 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意义 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.