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Traumatic brain injury and Alzheimer's disease

创伤性脑损伤和阿尔茨海默病

基本信息

批准号：
10347330
负责人：
CHU CHEN
金额：
$ 38.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2019-06-21 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347330
关键词：
Acceleration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Cell Nucleus Cells Clinical Clinical Research Closed head injuries Complex Cytoplasm DNA Binding Dementia Development Disease Progression Down-Regulation Elderly Etiology Genetic Transcription Gliosis Glutamate Receptor Impaired cognition Knowledge Memory Loss Metabolism Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Nuclear Outcome Pathogenesis Pathologic Patients Production RNA Splicing RNA-Binding Proteins Resistance Risk Factors Role Senile Plaques Signal Pathway Signal Transduction Synapses Testing Transgenic Mice Transgenic Organisms Traumatic Brain Injury Wild Type Mouse abeta deposition amyloid formation cerebral atrophy chronic traumatic encephalopathy cytokine early onset extracellular frontotemporal lobar dementia-amyotrophic lateral sclerosis hyperphosphorylated tau knock-down mild traumatic brain injury mouse model neuroinflammation neuropathology overexpression prevent protein TDP-43 response small hairpin RNA tau phosphorylation tau-1 therapeutic target

项目摘要

Summary Alzheimer's disease (AD) is the most common cause of dementia in the elderly and a majority of AD cases is sporadic without known causes. While the etiology of AD is multifactorial and complex, growing evidence suggests that traumatic brain injury (TBI) is a risk factor for development of AD and dementia. Repetitive TBI causes chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease. Pathological TDP- 43 inclusions are one of the important hallmarks of neuropathology in CTE. Clinical studies reveal that a significant number of AD patients with various pathological subtypes display pathological TDP-43 inclusions. These similarities and overlap in neuropathology between CTE and AD suggest that CTE is a TBI-triggered AD- like neurodegenerative disease. TDP-43 is a DNA and RNA binding protein shuttled between the cytoplasm and the nucleus that regulates nuclear transcription, RNA splicing, and metabolism. However, our understanding of TDP-43 in AD neuropathology is still limited. In particular, it is not clear whether there are a linkage or interactions between TDP-43 aggregation and Aβ formation or p-tau and how TBI induces excessive TDP-43 expression, resulting in its aggregation and mislocalization. Our previous studies demonstrate that repetitive mild closed head injury (mCHI) in mice results in AD-like neuropathological changes, including robust TDP-43 production and p-tau. Importantly, our preliminary results show that a single mCHI accelerated accumulation of Aβ plaques and gliosis and increased production of TDP-43 and p-tau in APP transgenic (TG) mice, suggesting that TBI accelerates and exacerbates AD neuropathology and promotes progression. Particularly, we observed that knockdown of TDP-43 by shRNA silencing prevented repetitive mCHI-induced p-tau and downregulation of glutamate receptor subunits. Thus, we hypothesize that TBI-induced excessive expression of TDP-43 is an important mechanism of the pathogenesis and neuropathology in AD. In specific aim 1, we will test the prediction that a single mCHI accelerates or exacerbates neuropathological changes in APP transgenic mice; in specific aim 2, we will test the hypothesis that TDP-43 overproduction is a key factor in TBI-induced acceleration and progression of AD neuropathology as well as synaptic and cognitive declines, and in specific aim 3, we will test the prediction that neuroinflammation triggered by TBI stimulates TDP-43 transcription and expression via the NF-κB signaling pathway. The outcome of the proposed application will reveal a previously undefined mechanism by which abnormal overproduction of TDP-43 induced by TBI contributes to AD neuropathology and will provide experimental evidence that TDP-43 may be a therapeutic target for preventing development of TBI- associated AD neuropathology and dementia or for halting disease progression.

摘要阿尔茨海默病(AD)是导致老年人痴呆的最常见原因，大多数AD病例是原因不明的零星的。虽然阿尔茨海默病的病因是多因素和复杂的，但越来越多的证据提示创伤性脑损伤是阿尔茨海默病和痴呆症发生的危险因素。重复性TBI 导致慢性创伤性脑病(CTE)，这是一种进行性神经退行性疾病。病理性TDP- 43包涵体是CTE神经病理的重要标志之一。临床研究表明，大量不同病理亚型的AD患者表现为病理性TDP-43包涵体。 CTE和AD在神经病理学上的这些相似之处和重叠表明CTE是一种脑损伤触发的AD- 就像神经退行性疾病。TDP-43是一种DNA和RNA结合蛋白，穿梭于细胞质和核调节核转录、核糖核酸剪接和新陈代谢的核。然而，我们对此的理解 TDP-43在AD神经病理中的作用仍有限。特别是，目前还不清楚是否存在联系或相互作用 Tdp-43聚集与β形成或p-tau之间的关系以及脑损伤如何诱导Tdp-43的过度表达导致了它的聚集和错位。我们之前的研究表明，重复性轻度封闭小鼠头部损伤(MCHI)导致AD样神经病变，包括TDP-43的强烈产生还有p-tau。重要的是，我们的初步结果表明，单个MCHI加速了Aβ斑块的积累在APP转基因(TG)小鼠中，胶质细胞增生和TDP-43和p-tau的产生增加，提示TBI 加速和加重阿尔茨海默病的神经病理，促进进展。特别是我们观察到，通过shRNA沉默抑制TDP-43抑制MCHI重复诱导的p-tau和下调ptau 谷氨酸受体亚基。因此，我们假设脑损伤诱导的TDP-43的过度表达是一种阿尔茨海默病发病机制和神经病理的重要机制。在具体目标1中，我们将检验预测单个MCHI加速或加重APP转基因小鼠的神经病理变化；目的2，我们将检验TDP-43过度生产是脑损伤诱导加速的关键因素的假说。阿尔茨海默病的神经病理进展以及突触和认知能力的下降，在特定的目标3，我们将测试颅脑损伤引发的神经炎症通过刺激TDP-43转录和表达的预测核因子-κB信号通路。拟议申请的结果将揭示以前未定义的颅脑损伤后TDP-43异常过表达参与AD神经病理及机制将提供实验证据，表明TDP-43可能是预防脑外伤发展的治疗靶点。与阿尔茨海默病相关的神经病理和痴呆或用于阻止疾病的进展。