Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression
Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression
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DOI：
10.1016/j.neuron.2019.12.015
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发表时间：
2020-03-18
期刊：
影响因子：
16.2
通讯作者：
Peng, Junmin
中科院分区：
文献类型：
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作者：
Bai, Bing;Wang, Xusheng;Peng, Junmin
阿尔茨海默病（AD）在痴呆之前显示出长时间的无症状阶段。我们通过质谱分析人脑中的14，513种蛋白质和34，173个磷酸化位点来表征AD阶段相关的分子网络，突出了17条通路中的173种蛋白质变化。改变的蛋白质在两个独立的群组中得到验证，显示出部分RNA依赖性。脑组织和脑脊液蛋白质组的比较揭示了生物标志物候选者。结合5xFAD小鼠分析，我们确定了15种A β相关蛋白（例如，MDK、NTN 1、SMOC 1、SLIT 2和HTRA 1）。5xFAD显示出与症状性AD相似的蛋白质组特征，但表现出自噬和干扰素应答的激活，并且缺乏人类特异性有害事件，例如神经营养因子和突触蛋白的下调。多组学整合优先考虑AD相关分子和途径，包括淀粉样蛋白级联、炎症、补体、WNT信号传导、TGF-β和BMP信号传导、脂质代谢、铁稳态和膜转运。一些A β相关蛋白与淀粉样斑块共定位。因此，多层组学方法鉴定了AD进展期间的蛋白质网络。
Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 A beta-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-beta and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some A beta-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.