Abeta oligomers (ADDLs) in Alzheimers Disease pathology

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性和不合时宜的胎儿痴呆。 其原因尚不清楚，但与突触病理学存在相关性，这可能是认知退化的原因。 我们和最近其他人提出，AD中的突触病理是由突触活性Abeta寡聚体引起的，我们称之为ADDLs。 寡聚体假说得到了来自多个实验室的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搅拌器产生的低聚物的研究。 本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，本研究旨在确定人体样本中ADDL的发生率和毒理学水平。 目的1：定量人类AD受试者中ADDL的发生。 我们将确定存在的ADDL的结构形式，它们在原位的分布，以及它们在脑、CSF和血浆中的丰度。 目的2：评价人ADDL的中枢神经系统毒性。 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，并测试人类ADDL结合导致突触病理学的预测。 为了表征人ADDL，我们已经开发了灵敏的ADDL抗体和免疫测定。 所提出的实验将扩展初步发现，其表明（i）ADDL存在于人类皮层中并且在AD中增加多达70倍（ii）ADDL在细胞外起作用并且在特定的突触后末端处与质膜结合（iii）突触结合的ADDL改变突触稳态，引起突触前和突触后末端的异常生长以及异位树突棘的形成。 这项研究将提供ADDL假说的第一个临床相关评估。 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）在大量受试者中测试痴呆和ADDL之间的相关程度，包括轻度认知障碍（MCI）和早期至中期AD;（2）开发使用ADDL作为最佳靶点的阿尔茨海默病治疗和诊断新方法。

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.