Alzheimer-Like Pathologies Following Traumatic Brain Injury in Older Individuals

描述（由申请人提供）：越来越多的证据表明，创伤性脑损伤（TBI）病史会增加患阿尔茨海默病（AD）的风险。联系这两种疾病状态的病理线索来自于对淀粉样蛋白- β (A2)斑块的观察，这是AD的标志性病理，可以在TBI后数小时内在患者中发现。此外，可以观察到过多的斑块，甚至在初始创伤后数十年持续存在。最近，我们已经确定A2-降解酶，neprilysin，可能在斑块的出现中起重要作用。研究还表明，单次脑外伤可导致神经原纤维缠结的延迟出现（阿尔茨海默病的另一个标志性病理），这是这两种疾病状态之间联系的重要证据。虽然主要在年轻人中研究了创伤性脑损伤后的ad样病理，但对于老年大脑如何对这些病理的创伤作出反应知之甚少。利用位于英国格拉斯哥的一个独特的人脑档案，我们建议检查老年人死后的脑组织，以寻找脑外伤后的ad样病理。具体来说，我们的目标是1。检查60岁以上持续性脑外伤患者阿尔茨海默病的标志性病理（A2斑块和nft）。2. 应用免疫组织化学和免疫组化技术检测60岁以上TBI患者A2降解酶neprilysin水平。研究溶瘤素基因载脂蛋白E （ApoE）基因多态性在预测60岁以上脑外伤患者淀粉样蛋白2斑块形成中的影响。由于阿尔茨海默病主要是一种衰老疾病，我们假设老年人在脑外伤后更容易发生类似阿尔茨海默病的病理。探索这些机制可能为改善临床管理和为这一独特的个体亚群开发治疗机会提供重要的基础。

DESCRIPTION (provided by applicant): Mounting evidence suggests a history of traumatic brain injury (TBI) can increase the risk of developing Alzheimer's disease (AD). A pathological clue linking these two disease states came with the observation that amyloid-beta (A2) plaques, a hallmark pathology of AD, could be found in patients within hours following TBI. Furthermore, excessive plaques can be observed, persisting even decades after the initiating trauma. More recently, we have identified that the A2- degrading enzyme, neprilysin, may play an important role in the emergence of plaques. It has also been demonstrated that just a single TBI can induce the delayed emergence of neurofibrillary tangles (the other hallmark pathology of AD) and stands as important evidence in the link between these two disease states. While AD-like pathologies after TBI have been studied primarily in younger adults, little is known about how the aged brain responds to trauma with regard to these pathologies. Using a unique human brain archive based in Glasgow, UK, we propose to examine post-mortem brain tissue of elderly individuals for AD-like pathologies following TBI. Specifically, we aim to 1. Examine for the hallmark pathologies of Alzheimer's disease (A2 plaques and NFTs) in individuals aged 60+ who have sustained a TBI. 2. Examine of A2 degrading enzyme, neprilysin, in individuals aged 60+ who have sustained a TBI, using immunohistochemistry and 3. Examine of the influence of polymorphisms of both the neprilysin gene Apolipoprotein E (ApoE) gene in predicting amyloid-2 plaque formation in individuals aged 60+ who have sustained a TBI. As AD is predominantly a disease of ageing, we hypothesize that older individuals will be have increased vulnerability to developing AD-like pathology post-TBI. Exploration of these mechanisms may provide an important basis for improving the clinical management and developing therapeutic opportunities for this unique subgroup of individuals. ) PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD). Both Hallmark pathologies of AD - A2 plaques and neurofibrillary tangles, have been found following TBI. Preliminary data suggests older individuals may be an increased risk of these TBI-induced pathologies. Using a unique human brain archive, we propose to examine older individuals for AD-like pathologies following TBI. Potential findings may explain the worsened neurocognitive outcomes observed following TBI in older patients. Understanding the mechanistic basis of these processes is vital in the drive towards targeted therapeutic intervention - particularly as novel AD-therapies emerge into the clinical forum. )