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.

概括阿尔茨海默氏病（AD）是古老的痴呆症最常见的原因，大多数AD病例是零星，没有已知原因。虽然AD的病因是多因素和复杂的，但越来越多的证据表明创伤性脑损伤（TBI）是发展AD和痴呆症的危险因素。重复的TBI 引起慢性创伤性脑病（CTE），一种进行性神经退行性疾病。病理TDP- 43个夹杂物是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TDP-43夹杂物。 CTE和AD之间神经病理学的这些相似之处和重叠表明CTE是TBI触发的AD- 像神经退行性疾病一样。 TDP-43是DNA和RNA结合蛋白，该蛋白在细胞质和调节核转录，RNA剪接和代谢的核us。但是，我们对 AD神经病理学中的TDP-43仍然有限。特别是，尚不清楚是否存在链接还是互动在TDP-43聚集和Aβ形成或P-TAU之间，TBI如何诱导TDP-43表达过多，导致其聚集和错误定位。我们以前的研究表明，重复的轻度关闭小鼠的头部损伤（MCHI）导致AD样神经病理学变化，包括强大的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的神经胶质病以及P-TAU的产生增加，这表明TBI 加速并加剧AD神经病理学并促进进展。特别是，我们观察到通过shRNA沉默敲低TDP-43 谷氨酸受体亚基。这，我们假设TBI诱导的TDP-43的过量表达是 AD中的发病机理和神经病理学的重要机制。在特定目标1中，我们将测试预测单个MCHI会加速或加剧APP转基因小鼠的神经病理变化；具体 AIM 2，我们将检验以下假设：TDP-43过量生产是TBI诱导的加速度和 AD神经病理学以及突触和认知能力下降的进展，在特定目标3中，我们将测试 TBI触发的神经炎症的预测刺激了TDP-43转录和表达 NF-κB信号通路。拟议申请的结果将揭示先前未定义的 TBI诱导的TDP-43异常生产异常的机制有助于AD神经病理学和将提供实验证据，表明TDP-43可能是防止TBI发展发展的治疗靶标相关的AD神经病理学和痴呆症或用于制止疾病进展。