Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.
Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.
复制标题
DOI：
10.1073/pnas.1811411115
复制
发表时间：
2018-10-02
影响因子：
11.1
通讯作者：
Gan L
中科院分区：
文献类型：
--
作者：
Sayed FA;Telpoukhovskaia M;Kodama L;Li Y;Zhou Y;Le D;Hauduc A;Ludwig C;Gao F;Clelland C;Zhan L;Cooper YA;Davalos D;Akassoglou K;Coppola G;Gan L
迟发性阿尔茨海默病是痴呆症最常见的形式。一种罕见的小胶质细胞表达基因的半合子变异，触发了髓样细胞上表达的受体2(TREM2)，显著增加了晚发性阿尔茨海默病的风险。这种变异被认为会导致功能丧失，导致TREM2单倍体功能不全。TREM2单倍体功能不全对小胶质细胞功能和tau病理的影响是该领域的主要空白。我们发现，与完全TREM2缺乏的保护作用相反，TREM2单倍体不足会加剧tau病理、炎症和疾病后期的萎缩。TREM2部分缺失和完全缺失的不同影响是TREM2靶向治疗策略的重要考虑因素。阿尔茨海默病(AD)是最常见的痴呆形式，其特征是淀粉样斑块和过度磷酸化的tau聚集体异常堆积，以及小胶质细胞增生。触发髓样细胞上表达的受体2(TREM2)的半合子错义变异与发生迟发性AD的风险增加相关。这些变异被认为会导致功能丧失，类似于TREM2单倍体功能不全。然而，TREM2单倍体功能不全对tau病理和小胶质细胞功能的影响尚不清楚。我们报道了部分和完全缺失TREM2对小胶质细胞功能和tau相关缺陷的影响。体内成像显示，与老年TREM2-KO小鼠的小胶质细胞相比，TREM2单倍体缺陷老年小鼠的小胶质细胞在损伤反应中表现出更大的损伤。在表达突变的人tau的转基因小鼠中，TREM2单倍性不足，但不完全丧失TREM2，增加了tau的病理改变。此外，尽管完全缺乏TREM2可以预防tau介导的小胶质细胞激活和萎缩，但TREM2单倍性不足增加了促炎标记物的表达，并在疾病晚期加剧了萎缩。TREM2的部分缺失和完全缺失对小胶质细胞功能和tau病理的不同影响为了解TREM2在AD发病机制中的关键作用提供了重要的见解。
Late-onset Alzheimer’s disease is the most common form of dementia. A rare hemizygous variant in a microglial-expressed gene, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), significantly increases risk for late-onset Alzheimer’s disease. This variant is thought to cause loss of function, inducing TREM2 haploinsufficiency. The ramifications of TREM2 haploinsufficiency on microglial function and tau pathology are major gaps in the field. We find that, in contrast to the protective effects of complete TREM2 deficiency, TREM2 haploinsufficiency exacerbates tau pathology, inflammation, and atrophy at a late stage of disease in a mouse model of tauopathy. The differential effects of partial and complete loss of TREM2 are important considerations for TREM2-targeted therapeutic strategies. Alzheimer’s disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.
登录
查看更多内容
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：
56.9
作者：
Nimmerjahn, A;Kirchhoff, F;Helmchen, F
通讯作者：
Helmchen, F
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
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
DOI：
10.1073/pnas.1710311114
发表时间：
2017-10-24
影响因子：
11.1
作者：
Leyns CEG;Ulrich JD;Finn MB;Stewart FR;Koscal LJ;Remolina Serrano J;Robinson GO;Anderson E;Colonna M;Holtzman DM
通讯作者：
Holtzman DM