THE HUNT FOR SYNAPTIC INTERACTORS OF ABETA

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 阿尔茨海默病患者的认知障碍与新皮质和边缘系统的突触丢失密切相关。 尽管在实验模型中已经广泛研究了聚集的淀粉样β寡聚体在阿尔茨海默病中的神经毒性作用，但对这些聚集体在阿尔茨海默病光谱中的特征知之甚少。在这项研究中，对对照组和阿尔茨海默病患者的死后额叶皮质样本进行了分离，并分析了寡聚体和突触蛋白的水平。我们发现，寡聚体的水平与认知损害的严重程度(祝福信息-记忆-集中分数和微小精神状态)相关 检查)和突触标志物的丢失。突触囊泡蛋白(囊泡相关膜蛋白-2)和突触后蛋白(突触后密度-95)水平的降低与所分析的不同组分中低聚物的水平相关。发现与淀粉样β二聚体和五聚体有最强的关联。 免疫共沉淀和双标记实验支持淀粉样β蛋白和突触后密度-95在突触部位相互作用的可能性。同样，在表达高水平神经元淀粉样前体蛋白的转基因小鼠中，淀粉样β蛋白与突触后密度-95免疫共沉淀。伴随而来的是阿尔茨海默病患者和淀粉样前体蛋白转基因小鼠大脑中突触后蛋白Shank1和Shank3水平的下降。总而言之，这项研究表明，阿尔茨海默病患者大脑中淀粉样β蛋白寡聚体亚群的存在可能与选定突触蛋白的变化和认知障碍有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The cognitive impairment in patients with Alzheimer's disease is closely associated with synaptic loss in the neocortex and limbic system. Although the neurotoxic effects of aggregated amyloid-beta oligomers in Alzheimer's disease have been studied extensively in experimental models, less is known about the characteristics of these aggregates across the spectrum of Alzheimer's disease. In this study, postmortem frontal cortex samples from controls and patients with Alzheimer's disease were fractionated and analyzed for levels of oligomers and synaptic proteins. We found that the levels of oligomers correlated with the severity of cognitive impairment (blessed information-memory-concentration score and mini-mental state examination) and with the loss of synaptic markers. Reduced levels of the synaptic vesicle protein, vesicle-associated membrane protein-2, and the postsynaptic protein, postsynaptic density-95, correlated with the levels of oligomers in the various fractions analyzed. The strongest associations were found with amyloid-beta dimers and pentamers. Co-immunoprecipitation and double-labeling experiments supported the possibility that amyloid-beta and postsynaptic density-95 interact at synaptic sites. Similarly, in transgenic mice expressing high levels of neuronal amyloid precursor protein, amyloid-beta co-immunoprecipitated with postsynaptic density-95. This was accompanied by a decrease in the levels of the postsynaptic proteins Shank1 and Shank3 in patients with Alzheimer's disease and in the brains of amyloid precursor protein transgenic mice. In conclusion, this study suggests that the presence of a subpopulation of amyloid-beta oligomers in the brains of patients with Alzheimer's disease might be related to alterations in selected synaptic proteins and cognitive impairment.