Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
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DOI：
10.1038/s41593-021-00999-y
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发表时间：
2022-03
影响因子：
25
通讯作者：
Seyfried NT
中科院分区：
文献类型：
--
作者：
Johnson ECB;Carter EK;Dammer EB;Duong DM;Gerasimov ES;Liu Y;Liu J;Betarbet R;Ping L;Yin L;Serrano GE;Beach TG;Peng J;De Jager PL;Haroutunian V;Zhang B;Gaiteri C;Bennett DA;Gearing M;Wingo TS;Wingo AP;Lah JJ;Levey AI;Seyfried NT
阿尔茨海默病 (AD) 大脑中被破坏的生物过程仍未完全了解。在这项研究中，我们分析了 1000 多个脑组织的蛋白质组，揭示了新的 AD 相关蛋白质共表达模块，这些模块在队列和大脑区域中高度保留。近一半的蛋白质共表达模块，包括 AD 中显着改变的模块，在来自相同群体和大脑区域的 RNA 网络中没有观察到，这凸显了 AD 的蛋白质病理性质。蛋白质组网络特有的两个这样的 AD 相关模块包括一个与 MAPK 信号传导和代谢相关的模块以及一个与基质体相关的模块。基质体模块受到 APOE ε4 等位基因的影响，但与神经病理学调整后的认知下降率无关。相比之下，MAPK/代谢模块与认知能力下降的速度密切相关。蛋白质组特有的疾病相关模块是 AD 有希望的治疗靶点和生物标志物的来源。作者分析了 1,000 多个脑组织中 8,600 多种蛋白质的水平，得出了一致的 AD 脑蛋白质共表达网络，该网络说明了 AD 中发生的复杂性和多种病理过程，其中许多过程并未在 RNA 水平上反映出来。
The biological processes that are disrupted in the Alzheimer’s disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD. The authors analyzed the levels of more than 8,600 proteins across more than 1,000 brain tissues to arrive at a consensus AD brain protein co-expression network that illustrates the complexity and multiple pathological processes that occur in AD, many of which are not reflected at the RNA level.
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DOI：
10.1093/biostatistics/kxr054
发表时间：
2012-04
期刊：
Biostatistics (Oxford, England)
影响因子：
--
作者：
Hansen KD;Irizarry RA;Wu Z
通讯作者：
Wu Z
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Boyle PA;Yu L;Wilson RS;Leurgans SE;Schneider JA;Bennett DA
通讯作者：
Bennett DA
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA