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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.

总结阿尔茨海默氏病（AD）是老年人痴呆症的最常见原因，并且大多数AD病例是没有已知原因的偶发性。虽然AD的病因是多因素和复杂的，但越来越多的证据表明，表明创伤性脑损伤（TBI）是AD和痴呆发展的危险因素。重复性TBI 导致慢性创伤性脑病（CTE），一种进行性神经退行性疾病。病理性TDP- 43包涵体是CTE神经病理学的重要标志之一。临床研究表明，大量具有各种病理亚型的AD患者显示病理性TDP-43包涵体。 CTE和AD之间的神经病理学的这些相似性和重叠表明CTE是TBI触发的AD。比如神经退行性疾病TDP-43是一种DNA和RNA结合蛋白，穿梭于细胞质之间，调节核转录、RNA剪接和新陈代谢的细胞核。然而，我们对 TDP-43在AD神经病理学中的作用仍然有限。特别是，不清楚是否存在联系或相互作用 TDP-43聚集和Aβ形成或p-tau之间的关系以及TBI如何诱导过度TDP-43表达，导致其聚集和错误定位。我们以前的研究表明，重复性轻度闭合小鼠头部损伤（mCHI）导致AD样神经病理学变化，包括强烈的TDP-43产生和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， APP转基因（TG）小鼠中TDP-43和p-tau的产生增加，表明TBI 加速和加重AD神经病理学并促进进展。我们特别注意到，通过shRNA沉默敲低TDP-43阻止了重复的mCHI诱导的p-tau蛋白和谷氨酸受体亚单位因此，我们假设TBI诱导的TDP-43的过度表达是一种抑制肿瘤生长的机制。 AD发病机制和神经病理学的重要机制。在具体目标1中，我们将测试预测单个mCHI加速或加剧APP转基因小鼠的神经病理学变化;具体而言，目标2，我们将检验TDP-43生产过剩是TBI诱导加速的关键因素的假设， AD神经病理学的进展以及突触和认知下降，并且在具体目标3中，我们将测试由TBI触发的神经炎症刺激TDP-43的转录和表达的预测， NF-κB信号通路。拟议申请的结果将揭示一个以前未定义的 TBI诱导的TDP-43异常过量产生导致AD神经病理学的机制，将提供实验证据，表明TDP-43可能是预防TBI发展的治疗靶点。相关的AD神经病理学和痴呆或阻止疾病进展。