TRAUMATIC BRAIN INJURY AND ALZHEIMERS DISEASE

阿尔茨海默病(AD)是一种遗传和表型不同的疾病，原因是 多种病因在手术上被定义为进行性痴呆，在患者的大脑中有丰富的富含Abeta的老年斑(SP)和富含tau的神经原纤维缠结(NFT)，但超过50%的AD患者还显示由α-突触核蛋白形成的路易小体(Lbs)。虽然大多数AD是零星的，但对AD的非遗传因素的认识差距限制了通过将环境AD风险因素降至最低而延迟其发病/病程的努力。值得注意的是，我们最近报道了首次在转基因(TG)小鼠AD样淀粉样变性(Tg2576或APPswe)模型中的实验数据，该模型将创伤性脑损伤(TBI)与 使用一种新的轻度重复脑损伤(MrTBI)范例积累Abeta和氧化应激。因此，我们假设，TBI通过增加氧化应激和使个体易患AD而增加AD SPS、NFT和可能的LBS的形成。基于这一点和本计划项目赠款(PPG)当前资金周期的额外进展，我们将研究主要AD损害(SPS、NFT、LBS)的新的TG小鼠模型，以描绘由脑损伤激活的导致AD样表型的神经退变途径。这将包括在更强大的、最近开发的AD样淀粉样变性TG小鼠模型以及特异性积累Abeta11-40/42(在AD的发病机制中被低估)的TG小鼠模型中进行的mrTBI研究，以及最近开发的tau和AS内含物与Abeta淀粉样变性TG小鼠杂交的TG小鼠模型。因此，在这里提出的目标中，我们将检验我们的假设，即在新的TG小鼠模型中，TBI通过增加氧化应激并加速SPS、NFT和LBS的形成而增加发生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.