CELLULAR CHANGES ALTERING SYNAPTIC CONNECTIVITY IN PRECLINICAL AD

临床前 AD 中细胞变化改变突触连接

• 批准号: 8509203
• 负责人: STEPHEN W SCHEFF
• 金额: $ 30.72万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509203
• 关键词: Actin-Binding Protein; Actins; Adult; Affect; Alzheimer' s Disease; Amyloid; Antioxidants; Area; Binding; Biochemical; Biological Markers; Brain region; Clinical; Cognition; Cognitive; Cytoskeletal Proteins; Data; Dementia; Development; Disease; Disease Progression; Early Diagnosis; Enzymes; Etiology; Event; Free Radicals; Functional disorder; Hippocampal Formation; Hippocampus (Brain); Histopathology; Impaired cognition; Individual; Lead; Link; Literature; Maintenance; Medial; Microtubules; Mission; Mitochondria; Molecular; NADPH Oxidase; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Oxidants; Oxidative Stress; Pathology; Play; Principal Investigator; Process; Production; Proteins; Reactive Oxygen Species; Research Support; Role; Sampling; Seminal; Source; Staging; Structural Protein; Subcellular Fractions; Symptoms; Synapses; Synaptic plasticity; System; Temporal Lobe; Testing; cofilin; cognitive function; cohort; dentate gyrus; design; entorhinal cortex; frontal lobe; human tissue; hyperphosphorylated tau; insight; mental state; mild cognitive impairment; neurofibrillary tangle formation; novel; oxidative damage; pre-clinical; prevent; programs; public health relevance; research study; synaptic failure; tau Proteins; tau aggregation

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.

描述（由申请人提供）：阿尔茨海默氏病（AD）在中枢神经系统中表现出严重的病理变化，包括淀粉样蛋白水平升高，高磷酸化TAU和突触损失。突触功能障碍是该疾病的标志，它与AD进展过程中的认知能力和痴呆症水平相关。目前尚不清楚为什么在AD的早期阶段减少突触数以及如何与病理的其他特征相关联。我们认为，氧化损伤和微管/肌动蛋白变化是AD和突触功能障碍基础的早期事件。越来越多的证据表明，内侧颞叶（MTL）是受影响的大脑的最早区域，可能为疾病进展提供重要的线索。我们的假设是，在MTL启动突触可塑性丧失的MTL中发生了多种不同的细胞变化，导致认知下降和临床AD发作。提出的实验将在突触蛋白，氧化应激和结构蛋白方面评估该大脑区域的变化。研究对来自纵向的验尸样本进行了简短的验尸样本进行了详细的认知测试。将具有柔滑的轻度认知障碍（AMCI）的个体与临床上没有认知障碍（NCI）的个体进行比较。 NCI组进一步归类为病理学非常低的个体（LP-NCI）或组织病理学高（AD水平）（HP-NCI）。当前的文献表明，HP-NCI代表临床前AD的个体。目标一个评估不同键突触蛋白与MTL中氧化应激之间的直接关系。目标两个探针是否在疾病进展过程中是否有NADPH-氧化酶（NOX）活性及其亚基发生变化，以及它如何与突触蛋白的变化和可溶性β的变化相关。 NOX酶通常在整个中枢神经系统中表达，并且是自由基的关键非单位方面来源。第三个目标探讨了关键的细胞骨架蛋白（例如肌动蛋白结合蛋白cofilin和tau）是否会增加MTL的增加，并改变不同水平的关键突触蛋白。成功完成拟议的研究将揭示有关AD进展早期阶段的机制的新见解，并有助于理性疗法的发展。