CELLULAR CHANGES ALTERING SYNAPTIC CONNECTIVITY IN PRECLINICAL AD

描述（由申请人提供）：阿尔茨海默病（AD）在中枢神经系统中表现出严重的病理改变，包括淀粉样蛋白水平升高、tau蛋白过度磷酸化和突触丧失。突触功能障碍是阿尔茨海默病的一个标志，它与阿尔茨海默病进展过程中的认知能力和痴呆水平有关。目前尚不清楚为什么突触数量在阿尔茨海默病的早期阶段减少，以及它如何与病理的其他特征联系起来。我们认为氧化损伤和微管/肌动蛋白改变是阿尔茨海默病进展的早期事件，是突触功能障碍的基础。越来越多的证据表明，内侧颞叶（MTL）是最早受影响的大脑区域，可能为疾病的进展提供重要线索。我们的假设是，MTL中发生了多种不同的细胞变化，引发突触可塑性的丧失，导致认知能力下降和临床AD的发病。拟议的实验将评估在突触蛋白、氧化应激和结构蛋白方面大脑区域的变化。这些研究是在短期的死后样本中进行的，这些样本来自纵向跟踪的个体，并进行了详细的认知测试。患有遗忘性轻度认知障碍（aMCI）的个体将与临床无认知障碍（NCI）的个体进行比较。NCI组进一步分为极低病理（LP- NCI）或高（AD水平）组织病理学（HP-NCI）的个体。目前的文献表明，HP-NCI代表了临床前AD患者。目的一探讨MTL中不同关键突触蛋白与氧化应激的直接关系。目的两个探针nadph氧化酶（NOX）活性及其亚基是否在疾病进展过程中发生变化，以及它如何与突触蛋白和可溶性A β的变化相关联。氮氧化物酶通常在整个中枢神经系统中表达，是自由基的关键非线粒体来源。第三个目的是探讨关键的细胞骨架蛋白，如肌动蛋白结合蛋白cofilin和tau蛋白，是否会增加MTL并改变关键突触蛋白的不同水平。这些研究的成功完成将揭示阿尔茨海默病早期发展机制的新见解，并有助于开发合理的治疗方法。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) manifests severe pathological changes in the CNS including increased levels of amyloid, hyperphosphorylated tau, and synaptic loss. Synaptic dysfunction is a hallmark of the disease that associates with the cognitive ability and level of dementia during the progression of AD. It is unclear why synaptic numbers are reduced in the early stages of AD and how it is linked to other features of the pathology. We believe that oxidative damage and microtubule/actin changes are early events in the progression of AD and underlie synaptic dysfunction. Increasing evidence suggests that the medial temporal lobe (MTL) is the earliest regions of the brain affected and may provide important clues to the progression of the disease. Our hypothesis is that multiple different cellular changes occur in the MTL initiating the loss of synaptic plasticity resulting in a declinein cognition and the onset of clinical AD. The proposed experiments will evaluate changes in this brain region in regards to synaptic proteins, oxidative stress, and structural proteins. Studies ar carried out on short post mortem samples from longitudinally followed individuals with detailed cognitive testing. Individuals with amnestic mild cognitive impairment (aMCI) will be compared to individuals that clinically show no cognitive impairment (NCI). The NCI group is further classified as individuals with very low pathology (LP- NCI) or high (AD levels) of histopathology (HP-NCI). Current literature suggests that HP-NCI represents individuals with preclinical AD. Aim one assess the direct relationship between different key synaptic proteins and oxidative stress in the MTL. Aim two probes whether or not NADPH-oxidase (NOX) activity and its subunits change during the disease progression and how it associates with changes in synaptic proteins and soluble A beta. The NOX enzyme is normally expressed throughout the central nervous system and is a key non-mitochondrial source of free radicals. The third aim explores whether or not key cytoskeletal proteins, such as the actin binding protein cofilin and tau, increase in the MTL and alters different levels of key synaptic proteins. Successful completion of the proposed studies will reveal new insights into the mechanisms underlying the very early stages in the progression of AD and contribute to the development of rational therapies.