Abeta oligomers (ADDLs) in Alzheimers Disease pathology

描述(申请人提供)：阿尔茨海默病(AD)是一种进行性和早产儿痴呆。其原因尚不清楚，但与突触病理存在关联，这可能是认知恶化的原因。我们和最近的其他人提出，AD的突触病理是由突触活性的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，证据几乎完全来自对模型系统和研究人员生成的低聚物的研究。 这项建议需要解决的问题：一个主要的问题是，支持ADTL假说的实验证据是否具有临床意义。因此，这项研究旨在确定ADDLS在人体样本中的出现水平和毒理学。 目的1：量化ADT1在人类AD患者中的发生。我们将确定ADDLS的结构形式，它们在原位的分布，以及它们在脑、脑脊液和血浆中的丰度。 目的2：评价人ADDLS的中枢毒理作用。我们将在大鼠海马区培养模型中确定ADTL结合位点与突触相关的位置，并测试人类ADDLS结合导致突触病理的预测。 为了确定人类ADDLS的特征，我们开发了敏感的ADTL抗体和免疫分析。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70倍；(Ii)ADDls在细胞外发挥作用，并与特定突触后终末的质膜结合；(Iii)突触结合的ADDls改变突触的动态平衡，导致突触前和突触后终末的异常生长和异位树突棘的形成。 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)在包括轻度认知障碍(MCI)和早中期阿尔茨海默病(AD)患者在内的一大批受试者中测试痴呆症和ADDLS之间的相关性；(2)开发以ADDLS为最佳靶点的阿尔茨海默氏症治疗和诊断的新方法。

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.