Abeta oligomers (ADDLs) in Alzheimers Disease pathology

阿尔茨海默病病理学中的 Abeta 寡聚物 (ADDL)

• 批准号: 6678227
• 负责人: WILLIAM L KLEIN
• 金额: $ 33.05万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678227
• 关键词: Alzheimer's disease; binding sites; blood; brain; cerebrospinal fluid; confocal scanning microscopy; dendrites; enzyme linked immunosorbent assay; fluorescence microscopy; high performance liquid chromatography; human tissue; immunocytochemistry; immunologic assay /test; in situ hybridization; laboratory rat; neuropathology; neurotoxins; posttranslational modifications; protein localization; protein structure; synapses; synaptogenesis; tissue /cell culture; transmission electron microscopy; western blottings

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive and untimely fetal dementia. Its cause is not yet known, but a correlation exists with synaptic pathology, which may be responsible for cognitive deterioration. We, and recently others, have proposed that synaptic pathology in AD is caused by synaptically active Abeta oligomers, which we have called ADDLs. The oligomer hypothesis is supported by compelling evidence from multiple laboratories. The evidence, however, comes almost exclusively from studies with model systems and investigator-generated oligomers. Need addressed by this proposal: A major concern is whether experimental evidence that favors the ADDL hypothesis is clinically relevant. This study therefore is designed to determine the level of occurrence and toxicology of ADDLs in human samples. AIM 1: Quantify ADDL occurrence in human subjects AD. We will determine the structural forms of ADDLs that are present, their distribution in situ, and their abundance in brain, CSF, and plasma. AIM 2: Evaluate the CNS toxicology of human ADDLs. We will determine where ADDL binding sites are found in relation to synapses in rat hippocampus culture models and test the prediction that binding of human ADDLs causes synaptic pathology. To characterize human ADDLs, we have developed sensitive ADDL antibodies and immunoassays. Proposed experiments will extend preliminary findings that indicate (i) ADDLs are present in human cortex and increase as much as 70-fold in AD (ii) ADDLs act extracellularly and bind to plasma membranes at particular post-synaptic terminals (iii) Synaptically-bound ADDLs alter synapse homeostasis, causing aberrant growth of pre- and post-synaptic terminals and the formation of ectopic dendritic spines. This study will provide the first clinically relevant evaluation of the ADDL hypothesis. In addition to testing a series of key predictions, it lays a foundation for two future goals: (1) To test the degree of correlation between dementia and ADDLs in a large group of subjects, including those with mild cognitive impairment (MCI) and early to middle-level AD; (2) To develop new approaches to Alzheimer's therapeutics and diagnostics using ADDLs as optimal targets.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性且早产的胎儿痴呆。 其原因尚不清楚，但与突触病理学存在相关性，这可能是导致认知能力下降的原因。 我们和其他人最近提出 AD 中的突触病理学是由突触活性 Abeta 寡聚体引起的，我们将其称为 ADDL。 寡聚物假说得到多个实验室令人信服的证据的支持。 然而，证据几乎完全来自模型系统和研究者生成的低聚物的研究。 该提案需要解决的问题：一个主要问题是支持 ADDL 假设的实验证据是否具有临床相关性。 因此，本研究旨在确定人类样本中 ADDL 的发生水平和毒理学。 目标 1：量化 AD 人类受试者中 ADDL 的发生率。 我们将确定存在的 ADDL 的结构形式、它们的原位分布以及它们在大脑、脑脊液和血浆中的丰度。 目标 2：评估人类 ADDL 的中枢神经系统毒理学。 我们将确定在大鼠海马培养模型中发现与突触相关的 ADDL 结合位点的位置，并测试人类 ADDL 的结合导致突触病理的预测。 为了表征人类 ADDL，我们开发了敏感的 ADDL 抗体和免疫测定法。 拟议的实验将扩展初步发现，表明（i）ADDLs存在于人类皮质中，并在AD中增加多达70倍（ii）ADDLs在细胞外起作用并与特定突触后末端的质膜结合（iii）突触结合的ADDLs改变突触稳态，导致突触前和突触后末端的异常生长以及突触后末端的异常生长和形成 异位树突棘。 这项研究将对 ADDL 假说进行首次临床相关评估。 除了测试一系列关键预测外，它还为未来的两个目标奠定了基础：（1）在一大群受试者中测试痴呆症与 ADDL 之间的相关程度，包括轻度认知障碍（MCI）和早中期 AD 受试者； (2) 使用 ADDL 作为最佳靶点开发阿尔茨海默病治疗和诊断的新方法。