Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Cell Rep. 2019 Jul 23;28(4):1103-1116.e4. doi: 10.1016/j.celrep.2019.06.073.
Asymptomatic and symptomatic Alzheimer's disease (AD) subjects may present with equivalent neuropathological burdens but have significantly different antemortem cognitive decline rates. Using the transcriptome as a proxy for functional state, we selected 414 expression profiles of symptomatic AD subjects and age-matched non-demented controls from a community-based neuropathological study. By combining brain tissue-specific protein interactomes with gene networks, we identified functionally distinct composite clusters of genes that reveal extensive changes in expression levels in AD. Global expression for clusters broadly corresponding to synaptic transmission, metabolism, cell cycle, survival, and immune response were downregulated, while the upregulated cluster included largely uncharacterized processes. We propose that loss of EGR3 regulation mediates synaptic deficits by targeting the synaptic vesicle cycle. Our results highlight the utility of integrating protein interactions with gene perturbations to generate a comprehensive framework for characterizing alterations in the molecular network as applied to AD.
无症状和有症状的阿尔茨海默病（AD）患者可能具有相当的神经病理学负担，但认知衰退率有显著差异。我们使用转录组作为功能状态的替代物，从一项基于社区的神经病理学研究中选择了 414 名有症状 AD 患者和年龄匹配的非痴呆对照者的表达谱。通过将大脑组织特异性蛋白质相互作用组与基因网络相结合，我们确定了功能上不同的基因复合簇，这些基因簇揭示了 AD 中表达水平的广泛变化。广泛对应于突触传递、代谢、细胞周期、存活和免疫反应的簇的全局表达下调，而上调的簇包括很大程度上未被表征的过程。我们提出，EGR3 调节的丧失通过靶向突触小泡循环来介导突触缺陷。我们的结果强调了将蛋白质相互作用与基因扰动相结合以生成用于描述 AD 中分子网络改变的综合框架的实用性。
