TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.
TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.
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DOI：
10.1186/s13024-017-0216-6
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发表时间：
2017-10-16
影响因子：
15.1
通讯作者：
Lamb BT
中科院分区：
文献类型：
--
作者：
Bemiller SM;McCray TJ;Allan K;Formica SV;Xu G;Wilson G;Kokiko-Cochran ON;Crish SD;Lasagna-Reeves CA;Ransohoff RM;Landreth GE;Lamb BT
髓样细胞-2(TREM2)上表达的触发受体的遗传变异会增加患晚发性阿尔茨海默病(LOAD)和其他神经退行性疾病的风险。最近的研究揭示了TREM2在调节细胞外β-淀粉样蛋白(A-β)病理、髓系细胞聚集和AD炎症中的多方面作用，但对于TREM2在神经退行性疾病尤其是AD中调节细胞内微管相关蛋白tau(MAPT；tau)病理的作用知之甚少。在此，我们报告了TREM2缺乏导致加速和加剧tau过度磷酸化和聚集的人源化的tau病小鼠模型。TREM2缺乏还间接导致神经元应激激酶通路的戏剧性广泛失调。我们的结果表明，小胶质细胞TREM2的缺乏导致tau病理的加重，并伴随着激活的神经元应激蛋白激酶的广泛增加。这些发现为了解TREM2在调节Aβ和tau病理中的复杂、多方面的作用提供了新的见解。本文的在线版本(10.1186/s130240170216-6)包含补充材料，可供授权用户使用。
Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer’s Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies. The online version of this article (10.1186/s13024-017-0216-6) contains supplementary material, which is available to authorized users.
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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：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
--
作者：
Linnartz, Bettina;Wang, Yiner;Neumann, Harald
通讯作者：
Neumann, Harald
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
--
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
通讯作者：
Lamb BT
影响因子：
7.7
作者：
Pooler, Amy M.;Phillips, Emma C.;Lau, Dawn H. W.;Noble, Wendy;Hanger, Diane P.
通讯作者：
Hanger, Diane P.