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Mitochondrial TDP-43 in Alzheimer's Disease

阿尔茨海默病中的线粒体 TDP-43

基本信息

批准号：
9815609
负责人：
Xinglong Wang
金额：
$ 54.89万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2020-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9815609
关键词：
APP-PS1 Address Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyotrophic Lateral Sclerosis Behavioral Binding Biochemical Brain Brain Stem Cell Nucleus Cognition Cognitive deficits Complex Cytoplasm DNA Sequence Alteration Dementia Disease Progression Elderly Ensure Exhibits Experimental Models Frontotemporal Dementia Functional disorder Genetic Genus Hippocampus Hippocampus (Brain)Impairment Investigation Measurement Measures Mediating Mediator of activation protein Messenger RNA Mitochondria Molecular Mus NADH dehydrogenase (ubiquinone)Neocortex Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Nuclear Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Performance Pharmacology Pilot Projects Play Post-Translational Protein Processing Prevention Protein Biosynthesis Proteins Reporting Resolution Respiration Role Senile Plaques Severities Spinal Cord Symptoms Synapses Temporal Lobe Testing Tissues Toxic effect Transgenic Mice autosomal dominant mutation base cognitive function early onset effective therapy frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis improved mitochondrial dysfunction motor disorder motor neuron degeneration mouse model neuron loss neuropathology neurotoxicity novel novel therapeutic intervention prevent protein TDP-43 sensor spatiotemporal tau Proteins treatment strategy

项目摘要

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