NEUROPATHOLOGICAL CORRELATES OF OLIGOMERIC AMYLOID BETA

低聚淀粉样蛋白 Beta 的神经病理学相关性

• 批准号: 8448164
• 负责人: BRADLEY T. HYMAN
• 金额: $ 19.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8448164
• 关键词: Address; Age of Onset; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Antibodies; Biochemical; Biochemical Markers; Brain; Clinical; Cognition; DLG4 gene; Dementia; Dendritic Spines; Deposition; Disease; Elements; Equilibrium; Evaluation; Genetic; Genotype; Gliosis; Goals; Histologic; Histopathology; Human; Image; Imagery; Immunohistochemistry; Impaired cognition; Individual; Instruction; Laboratories; Lead; Learning; Link; Massachusetts; Measures; Methodology; Molecular Sieve Chromatography; Nerve Degeneration; Neurofibrillary Tangles; Pattern; Phenotype; Play; Preparation; Procedures; Process; Proteins; Research; Research Personnel; Role; Senile Plaques; Severities; Structure; Synapses; Syndrome; System; Techniques; Testing; Toxic effect; Western Blotting; density; monomer; neuropathology; neurotoxicity; programs; relating to nervous system; research study; thioflavine; tomography

The amyloid p-protein (Afi) is closely linked to the pathophysiological processes that lead to Alzheimer disease (AD), and likely are ultimately responsible for the neural system collapse that causes the clinical syndrome of dementia. However the mechanistic role of Afi and the form in which it is toxic remain controversial. One hypothesis is that the insoluble amyloid plaque itself is deleterious to the brain. Contrasting this argument is the hypothesis that the damage is caused by soluble Aft oligomers. The overall goal of his Project is to examine these two competing hypotheses critically and determine whether one or both are more likely. In this research plan, we propose three specific aims built around advances in biochemical and morphological techniques. To learn whether and how soluble A(3oligomers, monomers and/or plaque cores correlate with the histopathological changes (gliosis, Ap deposits, neurofibrillary tangles), we will quantify the levels of soluble oligomers and monomers by new Size Exclusion Chromatography and sensitive IP/Western techniques and correlate these findings with each subject's detailed neuropathological phenotype and with clinical information. A second approach to these questions will utilize a newly developed histological preparation that allows visualization of individual synaptic elements, fibrillar Ap, and oligomeric Ap simultaneously. We have observed that oligomeric Ap-directed antibodies reveal a "halo" around plaques that corresponds to the region around plaques that have diminished dendritic spine density. Furthermore, oligomeric Ap-directed antibodies demonstrate puncta that co-localize with PSD95 positive dendritic spines. These observations motivate an analysis of oligomeric Apand synaptic change that will take aim at fundamental mechanisms of Ap-associated synaptic loss. These studies will address a central unresolved question: how do soluble oligomeric forms relate to the fibrillar, histologically detected forms of Ap. Moreover, our experiments will also directly address whether Ap in cognitively normal controls who have Ap deposits differ from those in subjects with AD. By taking advantage of well characterized material from the MADRC Neuropathology Core's Brain Bank, Clinical Core evaluations, and Statistical Core expertise, we plan to test hypotheses directed at the relationship of Ap to cognitive impairment and neuronal toxicity. RELEVANCE (See instructions): Project 3 of the Massachusetts ADRC will test the competing hypotheses of the role of Ap protein and the form in which its toxicity is associated with cognitive dysfunction and Alzheimer's disease neuropathology.

p 淀粉样蛋白 (Afi) 与导致以下疾病的病理生理过程密切相关： 阿尔茨海默病（AD），并可能最终导致神经系统崩溃，从而导致 痴呆症的临床综合征。然而，Afi 的机制作用及其毒性形式 仍然存在争议。一种假设是不溶性淀粉样斑块本身对大脑有害。 与此论点形成对比的是，损伤是由可溶性 Aft 低聚物引起的假设。这 他的项目的总体目标是批判性地检验这两个相互竞争的假设，并确定是否 其中之一或两者的可能性更大。在本研究计划中，我们提出了围绕以下方面的进展建立的三个具体目标 生化和形态学技术。了解 A(3 低聚物、单体) 是否可溶以及如何可溶 和/或斑块核心与组织病理学变化（神经胶质增生、Ap沉积、神经原纤维 缠结），我们将通过新的尺寸排除来量化可溶性低聚物和单体的水平 色谱法和敏感的知识产权/西方技术，并将这些发现与每个受试者的 详细的神经病理学表型和临床信息。解决这些问题的第二种方法 将利用新开发的组织学制备方法，使单个突触可视化 同时。我们观察到寡聚Ap定向 抗体在斑块周围显示出一个“光环”，该光环对应于具有斑块周围区域的区域 树突棘密度减少。此外，寡聚Ap定向抗体证明了点 与 PSD95 阳性树突棘共定位。这些观察结果促使我们进行分析 寡聚 Apand 突触变化将针对 Ap 相关的基本机制 突触损失。这些研究将解决一个未解决的核心问题：可溶性寡聚体如何形成 与组织学检测到的纤维状 Ap 形式有关。而且，我们的实验也将直接 解决具有 Ap 沉积物的认知正常对照中的 Ap 是否与具有 Ap 沉积物的受试者不同 广告。通过利用来自 MADRC 神经病理学核心大脑的充分表征的材料 银行、临床核心评估和统计核心专业知识，我们计划测试针对 Ap与认知障碍和神经元毒性的关系。 相关性（参见说明）： 马萨诸塞州 ADRC 的项目 3 将测试 Ap 蛋白的作用和 其毒性与认知功能障碍和阿尔茨海默病神经病理学有关。