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: 8235897
• 负责人: BRADLEY T. HYMAN
• 金额: $ 21.31万
• 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/8235897
• 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.

淀粉样蛋白P蛋白（AFI）与导致的病理生理过程紧密相关 阿尔茨海默氏病（AD），最终可能是导致神经系统崩溃的原因 痴呆症的临床综合征。但是，AFI的机械作用及其有毒的形式 保持争议。一个假设是，不溶性淀粉样菌斑本身对大脑有害。 与该论点相反的是，损害是由可溶的船尾低聚物引起的。这 他的项目的总体目标是批判性地检查这两个竞争假设，并确定是否是否 一个或两个更有可能。在本研究计划中，我们提出了三个围绕进步的特定目标 生化和形态学技术。了解是否以及如何溶解A（3oligomers，单体 和/或斑块核与组织病理学变化相关（神经胶质变化，AP沉积，神经原纤维 缠结），我们将按新尺寸排除来量化可溶性低聚物和单体的水平 色谱和灵敏的IP/西方技术，并将这些发现与每个主题的发现相关联 详细的神经病理表型和临床信息。这些问题的第二种方法 将利用新开发的组织学制剂，允许可视化单个突触 元素，纤维纤维AP和低聚的元素同时。我们已经观察到寡聚AP导向 抗体显示斑块周围的“光晕”，与斑块周围的区域相对应 树突状脊柱密度降低。此外，寡聚AP指导的抗体表现出puncta 与PSD95阳性树突状棘突共定位。这些观察激发了对 寡聚公园突触变化将针对与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中心问题：可溶性寡聚形式如何 与原纤维，组织学检测到的AP的形式有关。而且，我们的实验也将直接 解决具有AP沉积的认知正常对照中的AP是否与受试者中的AP是否不同 广告。通过利用MADRC神经病理学核心的大脑的良好特征材料 银行，临床核心评估和统计核心专业知识，我们计划测试针对该假设 AP与认知障碍与神经元毒性的关系。 相关性（请参阅说明）： 马萨诸塞州ADRC的项目3将测试AP蛋白和AP蛋白作用的竞争假设 其毒性与认知功能障碍和阿尔茨海默氏病神经病理学有关的形式。