Traumatic brain injury and Alzheimer's disease

总结 阿尔茨海默病 (AD) 是老年人痴呆症的最常见原因，大多数 AD 病例是 零星发生且原因不明。尽管 AD 的病因是多因素且复杂的，但越来越多的证据表明 表明创伤性脑损伤（TBI）是 AD 和痴呆症发展的危险因素。重复性创伤性脑损伤 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 患者表现出病理性 TDP-43 包涵体。 CTE 和 AD 之间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 是一种在细胞质和细胞质之间穿梭的 DNA 和 RNA 结合蛋白。 调节核转录、RNA 剪接和代谢的细胞核。然而，我们的理解 TDP-43 在 AD 神经病理学中的应用仍然有限。特别是，尚不清楚是否存在联系或相互作用 TDP-43 聚集与 Aβ 形成或 p-tau 之间的关系以及 TBI 如何诱导 TDP-43 过度表达， 导致其聚集和错误定位。我们之前的研究表明，重复的温和关闭 小鼠头部损伤 (mCHI) 会导致类似 AD 的神经病理变化，包括 TDP-43 的大量产生 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 可防止重复 mCHI 诱导的 p-tau 和下调 谷氨酸受体亚基。因此，我们假设 TBI 诱导的 TDP-43 过度表达是一种 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 单一 mCHI 会加速或加剧 APP 转基因小鼠的神经病理学变化；具体来说 目标 2，我们将检验以下假设：TDP-43 过量生产是 TBI 引起的加速的关键因素，并且 AD 神经病理学的进展以及突触和认知能力下降，在具体目标 3 中，我们将测试 预测 TBI 引发的神经炎症通过刺激 TDP-43 转录和表达 NF-κB 信号通路。拟议申请的结果将揭示以前未定义的 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，证明 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。

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.