TRAUMATIC BRAIN INJURY AND ALZHEIMERS DISEASE

阿尔茨海默病（AD）是一种遗传和表型异质性疾病， 多种病因，其在操作上被定义为在受影响患者的脑中具有丰富的富含A β的老年斑（SP）和富含tau的神经元缠结（NFT）的进行性痴呆，但超过50%的AD患者还显示由α-突触核蛋白形成的路易体（LB）。虽然大多数AD是散发性的，但在理解AD的非遗传贡献方面的差距限制了通过最大限度地减少环境AD风险因素来延迟其发病/病程的努力。值得注意的是，我们最近报道了AD样A β淀粉样变性（Tg 2576或APPswe）转基因（TG）小鼠模型的第一个实验数据，该模型将创伤性脑损伤（TBI）与 使用新的轻度重复TBI（mrTBI）范例，观察Abeta和氧化应激的累积。因此，我们假设TBI通过增加氧化应激和使个体易患AD来增强AD SP、NFT和可能的LB的形成。基于这一点以及该计划项目资助（PPG）当前资助周期的其他进展，我们将研究主要AD病变（SP，NFT，LB）的新TG小鼠模型，以描绘由TBI激活的导致AD样表型的神经退行性通路。这将包括在更稳健的、最近开发的AD样A β淀粉样变性TG小鼠模型以及特异性积累A β 11 -40/42沉积物的TG小鼠模型（在AD的发病机制中被低估）中的mrTBI研究，以及最近开发的与A β淀粉样变性TG小鼠杂交的tau和AS包涵体TG小鼠模型。因此，在本文提出的目的中，我们将检验我们的假设，即TBI通过增加氧化应激和加速新型TG小鼠模型中SP、NFT和LB的形成来增加发展AD神经变性的风险。

Alzheimer's disease (AD) is a genetically and phenotypically heterogeneous disorder due to multiple etiologies that is operationally defined as a progressive dementia with abundant Abeta-rich senile plaques (SPs) and tau-rich neurofibrillary tangles (NFTs) in the brains of affected patients, but more than 50% of AD patients also show Lewy bodies (LBs) formed by alpha-synuclein. Although most AD is sporadic, gaps in understanding non-genetic contributions to AD limit efforts to delay its onset/course by minimizing environmental AD risk factors. Significantly, we recently reported the first experimental data in a transgenic (TG) mouse model of AD-like Abeta amyloidosis (Tg2576 or APPswe) linking traumatic brain injury (TBI) to accumulations of Abeta and oxidative stress using a novel mild repetitive TBI (mrTBI) paradigm. Thus, we hypothesize that TBI augments formation of AD SPs, NFTs and possibly LBs by increasing oxidative stress and predisposing individuals to AD. Based on this and additional progress from the current funding cycle of this Program Project Grant (PPG), we will investigate new TG mouse models of major AD lesions (SPs, NFTs, LBs) to delineate neurodegenerative pathways activated by TBI that lead to an AD-like phenotype. This will include studies of mrTBI in more robust, recently developed, TG mouse models of AD-like Abeta amyloidosis as well as TG mouse models that specifically accumulate deposits of Abeta11-40/42 (which has been underestimated in the pathogenesis of AD), and recently developed TG mouse models of tau and AS inclusions crossed with the Abeta amyloidosis TG mice. Thus, in the Aims proposed here, we will test our hypothesis that TBI increases the risk for developing AD neurodegeneration by increasing oxidative stress and accelerating the formation of SPs, NFTs and LBs in novel TG mouse models.