Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models.
Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models.
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DOI：
10.1186/s13073-018-0530-9
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发表时间：
2018-03-29
期刊：
影响因子：
12.3
通讯作者：
Iijima KM
中科院分区：
文献类型：
--
作者：
Sekiya M;Wang M;Fujisaki N;Sakakibara Y;Quan X;Ehrlich ME;De Jager PL;Bennett DA;Schadt EE;Gandy S;Ando K;Zhang B;Iijima KM
阿尔茨海默病(AD)的主要特征是大脑淀粉样变性、神经炎症和脑血管病变，但这些特征之间的相互作用仍然知之甚少。我们之前的AD多尺度分子网络模型显示，TYROBP是与AD病理生理学密切相关的免疫和小胶质细胞特异性网络的关键驱动因素。最近的AD遗传学研究进一步发现了TREM2和TYROBP的致病突变。在这项研究中，我们通过整合来自转基因果蝇AD模型的信号和来自两个人类AD队列的转录组范围的基因共表达网络，系统地研究了Aβ、tau、TREM2和TYROBP之间的分子和病理相互作用。胶质细胞表达TREM2/TYROBP加剧了tau介导的神经退行性变，协同影响了迟发性AD的病理机制，而神经元Aβ42和神经胶质细胞TREM2/TYROBP协同改变了突触功能和免疫模块中的基因表达。通过这项研究产生的全面的病理和分子数据有力地验证了TREM2/TYROBP在驱动果蝇AD和AD相关表型的分子网络中的因果作用。本文的在线版本(10.1186/s13073-0180530-9)包含补充材料，可供授权用户使用。
Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts. Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD. The comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies. The online version of this article (10.1186/s13073-018-0530-9) contains supplementary material, which is available to authorized users.
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影响因子：
4.2
作者：
Forabosco P;Ramasamy A;Trabzuni D;Walker R;Smith C;Bras J;Levine AP;Hardy J;Pocock JM;Guerreiro R;Weale ME;Ryten M
通讯作者：
Ryten M
影响因子：
3.7
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
通讯作者：
Zhong Y
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：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y