Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently observed that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), is associated with exacerbated synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. We examined brain tissue from 33 subjects (7-10 per group). We pooled tissue from all subjects in each group for unbiased proteomic analyses followed by validation with individual case samples. Our analysis identified over 5500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.

中文翻译：

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阿尔茨海默氏病患者突触蛋白质组的比较分析，重点是APOE基因型。

阿尔茨海默氏病（AD）中突触的变性与认知能力下降密切相关，并且突触病理学有助于疾病的病理生理。我们最近观察到，散发性AD的最强遗传危险因素是载脂蛋白E epsilon 4（APOE4），与人类AD脑中突触丢失和寡聚淀粉状蛋白β的突触积累有关。为了开始了解AD中突触丢失的分子级联及其如何由APOE介导，并且为了获得了解AD中突触蛋白质组变化的知识的资源，我们进行了蛋白质组学筛选和突触神经小体制剂的系统计算机模拟分析来自人类AD的颞叶皮质和枕叶皮质以及具有已知APOE基因状态的对照受试者。我们检查了33名受试者的脑组织（每组7-10名）。我们汇集了每组所有受试者的组织，进行了无偏见的蛋白质组学分析，然后通过个案样本进行了验证。我们的分析确定了人类突触神经小体中的5500多种蛋白质，并突出了疾病，脑区和APOE相关的多种分子途径的变化，包括对突触和线粒体功能重要的蛋白质的AD含量降低，以及与神经免疫相互作用和细胞内信号传导。