THE HUNT FOR SYNAPTIC INTERACTORS OF ABETA

寻找 ABETA 突触相互作用因子

• 批准号: 8365876
• 负责人: ELIEZER MASLIAH
• 金额: $ 0.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8365876
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Biology; Brain; Characteristics; Co-Immunoprecipitations; Experimental Models; Funding; Fungal Genome; Grant; Impaired cognition; Label; Limbic System; Memory; National Center for Research Resources; Neocortex; Neurons; Patients; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Sampling; Severities; Site; Source; Synapses; Synaptic Vesicles; Transgenic Mice; United States National Institutes of Health; VAMP-2; cost; dimer; frontal lobe; mental state; neurotoxic; postsynaptic; presynaptic density protein 95; research study

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 阿尔茨海默病患者的认知功能障碍与新皮层和边缘系统的突触丢失密切相关。 虽然聚集的淀粉样蛋白-β寡聚体在阿尔茨海默病中的神经毒性作用已经在实验模型中进行了广泛的研究，但对阿尔茨海默病谱中这些聚集体的特征知之甚少。在这项研究中，从对照组和阿尔茨海默病患者的死后额叶皮层样本进行了分离和分析的低聚物和突触蛋白的水平。我们发现低聚物水平与认知障碍的严重程度（祝福信息-记忆-集中评分和简易精神状态）相关， 检查）和突触标记物的丢失。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的水平降低与分析的各个部分中的低聚物水平相关。最强的关联被发现与淀粉样蛋白β二聚体和五聚体。 免疫共沉淀和双标记实验支持淀粉样蛋白β和突触后密度-95在突触位点相互作用的可能性。类似地，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共免疫沉淀。这伴随着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Shank 1和Shank 3水平的下降。总之，这项研究表明，阿尔茨海默病患者大脑中淀粉样β低聚物亚群的存在可能与选定的突触蛋白和认知障碍的改变有关。