Mitochondrial TDP-43 in Alzheimer's Disease

阿尔茨海默病中的线粒体 TDP-43

• 批准号: 10766077
• 负责人: Xinglong Wang
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10766077
• 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.

项目总结