Comparative profiling of the synaptic proteome from Alzheimer's disease patients with focus on the APOE genotype
Comparative profiling of the synaptic proteome from Alzheimer's disease patients with focus on the APOE genotype
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DOI：
10.1186/s40478-019-0847-7
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发表时间：
2019-12-20
影响因子：
7.1
通讯作者：
Spires-Jones, Tara L.
中科院分区：
文献类型：
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作者：
Hesse, Raphael;Hurtado, Maica Llavero;Spires-Jones, Tara L.
阿尔茨海默病（AD）中突触的退化与认知能力下降密切相关，突触病理学有助于疾病的病理生理学。我们最近观察到，散发性 AD 的最强遗传风险因素，载脂蛋白 E epsilon 4 (APOE4)，与人类 AD 大脑中突触丧失加剧和寡聚淀粉样蛋白 β 突触积聚有关。为了开始了解 AD 突触丢失所涉及的分子级联反应以及 APOE 如何介导这种级联，并生成有关 AD 突触蛋白质组变化的知识资源，我们对人类 AD 颞叶和枕叶皮质以及具有已知 APOE 基因状态的对照受试者的突触神经体制剂进行了蛋白质组筛选和系统计算机分析。我们检查了 33 名受试者（每组 7-10 名）的脑组织。我们汇集了每组所有受试者的组织进行无偏见的蛋白质组学分析，然后用个体病例样本进行验证。我们的分析鉴定了人类突触神经体中超过 5500 种蛋白质，并强调了多种分子途径中与疾病、大脑区域和 APOE 相关的变化，包括 AD 中对突触和线粒体功能重要的蛋白质丰度减少，以及参与神经免疫相互作用和细胞内信号传导的蛋白质丰度增加。
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.