Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer's disease.
Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer's disease.
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DOI：
10.3389/fnagi.2022.935279
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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神经炎症信号传导已被确定为除了淀粉样β斑块（A β）和神经纤维缠结（NFT）之外的阿尔茨海默病（AD）的重要标志。然而，神经炎症的分子机制和生物学过程仍然不清楚，并没有很好地描绘使用转录组学数据。我们的目标是利用转录组学数据的整合网络分析来揭示AD中的核心神经炎症信号通路。从一个新的角度来看，通过研究弱激活的分子信号（而不是强激活的分子信号），我们开发了整合和系统生物学网络分析，以使用两个大规模转录组学数据集来揭示AD中潜在的核心神经炎症信号传导靶点和途径，即，马约诊所（77个对照和81个AD样品）和ROSMAP（97个对照和260个AD样品）。我们的分析确定了有趣的核心神经炎症信号通路，这是没有系统地报告在以前的研究AD。具体而言，我们确定了7类与AD相关并与病毒感染相关的信号传导途径：免疫应答、x-核心信号传导、细胞凋亡、脂质功能障碍、生物合成和代谢以及矿物质吸收信号传导途径。更有趣的是，病毒感染、免疫反应和x核心信号通路中的大多数基因都与炎症分子功能相关。x-core信号通路包括MAPK、Rap1、NF-κ B B、HIF-1、PI3 K-Akt、Wnt、TGF-β、Hippo和TNF等9种信号蛋白，表明x-core信号通路是低水平、弱激活的炎症反应和缺氧导致慢性神经退行性变的核心神经炎症信号通路。有趣的是，研究这些弱活化的神经炎症信号通路的详细信号级联，从而在慢性过程中引起神经变性，并因此发现有效治疗和预防AD的新的治疗靶点。潜在的核心神经炎症和相关的信号传导靶点和通路使用整合网络分析两个大规模的转录组学数据集的AD。
Neuroinflammation signaling has been identified as an important hallmark of Alzheimer’s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
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
影响因子：
5.3
作者：
Combs, CK;Johnson, DE;Landreth, GE
通讯作者：
Landreth, GE
影响因子：
14
作者：
通讯作者：
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