TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models.
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models.
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DOI：
10.1084/jem.20142322
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发表时间：
2015-03-09
期刊：
影响因子：
--
通讯作者：
Lamb BT
中科院分区：
文献类型：
--
作者：
Jay TR;Miller CM;Cheng PJ;Graham LC;Bemiller S;Broihier ML;Xu G;Margevicius D;Karlo JC;Sousa GL;Cotleur AC;Butovsky O;Bekris L;Staugaitis SM;Leverenz JB;Pimplikar SW;Landreth GE;Howell GR;Ransohoff RM;Lamb BT
Jay及其同事表明，TREM2缺乏减少了浸润大脑的巨噬细胞的数量，并在阿尔茨海默病小鼠模型中对疾病发病机制具有保护作用。髓样细胞上表达的触发受体2（TREM2）的变体赋予阿尔茨海默病（AD）和其他神经退行性疾病的高风险。然而，TREM2参与神经变性的细胞类型和机制仍有待建立。在这里，我们报告了TREM2在AD小鼠模型和人类AD组织中淀粉样蛋白沉积物周围的髓样细胞上上调。TREM2在CD45hiLy6C+骨髓细胞上检测到，但在P2RY12+实质小胶质细胞上未检测到。在TREM2缺陷的AD小鼠中，CD45hiLy6C+巨噬细胞几乎被消除，导致炎症减少并改善淀粉样蛋白和tau病理学。这些数据表明TREM2+巨噬细胞在AD发病机制中的功能重要作用以及TREM2在AD病理学中的意想不到的有害作用。这些发现对TREM2靶向疗法的未来发展具有直接意义。
Jay and colleagues show that TREM2 deficiency reduces the number of macrophages infiltrating the brain and is protective against disease pathogenesis in mouse models of Alzheimer’s disease. Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2’s involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45hiLy6C+ myeloid cells, but not on P2RY12+ parenchymal microglia. In AD mice deficient for TREM2, the CD45hiLy6C+ macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2+ macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.
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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
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：
10.6
作者：
Karch CM;Goate AM
通讯作者：
Goate AM
影响因子：
3.5
作者：
Riddell, David R.;Zhou, Hua;Jacobsen, J. Steve
通讯作者：
Jacobsen, J. Steve
影响因子：
15.1
作者：
Ulrich JD;Finn MB;Wang Y;Shen A;Mahan TE;Jiang H;Stewart FR;Piccio L;Colonna M;Holtzman DM
通讯作者：
Holtzman DM