Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain.
Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain.
复制标题
DOI：
10.1016/j.neurobiolaging.2018.04.019
复制
发表时间：
2018-09
影响因子：
4.2
通讯作者：
Newhouse SJ
中科院分区：
文献类型：
--
作者：
Carbajosa G;Malki K;Lawless N;Wang H;Ryder JW;Wozniak E;Wood K;Mein CA;Dobson RJB;Collier DA;O'Neill MJ;Hodges AK;Newhouse SJ
髓样细胞表达的触发受体2（TREM 2）基因中罕见的杂合编码变体，增加了发生迟发性阿尔茨海默病的风险，已被确定。我们研究了小鼠脑中Trem 2丢失的转录后果，以更好地了解其在疾病中的作用，使用Trem 2敲除小鼠和野生型小鼠的差异表达和共表达网络分析。我们从4个月和8个月时取样的皮质和海马体中生成RNA-Seq数据。使用脑细胞类型标记和本体富集，我们发现了具有细胞类型和/或功能标识的子网络。我们主要在4个月时发现了内皮基因富集子网络的变化，包括淀粉样前体蛋白基因向更核心的作用转变，以及其他细胞类型子网络的广泛破坏，包括具有神经元身份的子网络。我们揭示了Trem 2在内皮细胞稳态中的意想不到的潜在作用，超出了其作为小胶质细胞受体和信号传导中心的已知功能，表明免疫反应与痴呆症血管疾病之间存在潜在联系。
Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial gene-enriched subnetwork at 4 months, including a shift toward a more central role for the amyloid precursor protein gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub, suggesting an underlying link between immune response and vascular disease in dementia.
登录
查看更多内容
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
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.
影响因子：
4.4
作者：
Daws, MR;Sullam, PM;Seaman, WE
通讯作者：
Seaman, WE
影响因子：
4.2
作者：
Benitez BA;Jin SC;Guerreiro R;Graham R;Lord J;Harold D;Sims R;Lambert JC;Gibbs JR;Bras J;Sassi C;Harari O;Bertelsen S;Lupton MK;Powell J;Bellenguez C;Brown K;Medway C;Haddick PC;van der Brug MP;Bhangale T;Ortmann W;Behrens T;Mayeux R;Pericak-Vance MA;Farrer LA;Schellenberg GD;Haines JL;Turton J;Braae A;Barber I;Fagan AM;Holtzman DM;Morris JC;3C Study Group;EADI consortium;Alzheimer's Disease Genetic Consortium (ADGC);Alzheimer's Disease Neuroimaging Initiative (ADNI);GERAD Consortium;Williams J;Kauwe JS;Amouyel P;Morgan K;Singleton A;Hardy J;Goate AM;Cruchaga C
通讯作者：
Cruchaga C