TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.
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DOI：
10.1073/pnas.1710311114
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发表时间：
2017-10-24
影响因子：
11.1
通讯作者：
Holtzman DM
中科院分区：
文献类型：
--
作者：
Leyns CEG;Ulrich JD;Finn MB;Stewart FR;Koscal LJ;Remolina Serrano J;Robinson GO;Anderson E;Colonna M;Holtzman DM
阿尔茨海默病（AD）是痴呆症的最常见原因，并且是目前没有疾病改善治疗的主要公共卫生问题。迫切需要更好地了解患者神经变性的分子机制，以创造更好的治疗方案。最近，遗传研究发现了小胶质细胞受体中的新型AD风险变体，触发了髓样细胞2（TREM 2）上表达的受体。先前的研究表明，TREM 2功能的丧失导致淀粉样蛋白-β（Aβ）斑块相关毒性。相比之下，我们观察到TREM 2缺乏减轻神经炎症并在tau病理学的背景下防止脑萎缩。这些发现表明TREM 2和小胶质细胞在淀粉样蛋白与tau病理学的背景下具有双重作用，这对于考虑靶向TREM 2的潜在治疗是重要的。最近发现编码髓样细胞表达的触发受体2（TREM 2）的基因的变体会增加患阿尔茨海默病（AD）的风险。在大脑中，TREM 2主要在小胶质细胞上表达，并且其与AD的关联增加了越来越多的证据，表明先天免疫系统在AD起始和进展中的作用。到目前为止，研究已经发现TREM 2在对淀粉样蛋白病理学的响应中具有保护性，而导致TREM 2功能丧失的变体损害小胶质细胞信号传导并且是有害的。然而，TREM 2在tau病理学背景下的潜在作用尚未被表征。在这项研究中，我们将Trem 2 +/+（T2+/+）和Trem 2 −/−（T2−/−）小鼠与PS19人tau转基因系（PS）杂交，以研究TREM 2功能的丧失是否影响tau病理学、小胶质细胞对tau病理学的反应或神经变性。引人注目的是，与T2+/+PS小鼠相比，9月龄时，T2−/−PS小鼠表现出明显较少的脑萎缩，这是通过脑室扩大和保留内嗅区和梨状区的皮质体积来量化的。然而，对于磷酸化tau染色或不溶性tau水平，未观察到TREM 2依赖性差异。相反，与T2+/+PS小鼠相比，T2−/−PS小鼠在海马和梨状皮质中表现出显著减少的小胶质细胞增生。基因表达分析和免疫染色显示，T2−/−PS小鼠的小胶质细胞活化显著减弱，炎性细胞因子和星形胶质细胞增生水平较低。这些意想不到的发现表明，损害小胶质细胞TREM 2信号传导减少了神经炎症，并且在纯tau蛋白病的情况下对神经变性具有保护作用。
Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2. Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer’s disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2+/+ (T2+/+) and Trem2−/− (T2−/−) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2−/−PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2−/−PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex compared with T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2−/−PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.
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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：
11.2
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Cialic, Ron;Krasemann, Susanne;Murugaiyan, Gopal;Fanek, Zain;Greco, David J.;Wu, Pauline M.;Doykan, Camille E.;Kiner, Olga;Lawson, Robert J.;Frosch, Matthew P.;Pochet, Nathalie;El Fatimy, Rachid;Krichevsky, Anna M.;Gygi, Steven P.;Lassmann, Hans;Berry, James;Cudkowicz, Merit E.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
DOI：
10.1084/jem.20162125
发表时间：
2017-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ising C;Gallardo G;Leyns CEG;Wong CH;Jiang H;Stewart F;Koscal LJ;Roh J;Robinson GO;Remolina Serrano J;Holtzman DM
通讯作者：
Holtzman DM
影响因子：
25
作者：
Musiek, Erik S.;Holtzman, David M.
通讯作者：
Holtzman, David M.
DOI：
10.1084/jem.2016212505192017c
发表时间：
2017-07-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ising, Christina;Gallardo, Gilbert;Holtzman, David M
通讯作者：
Holtzman, David M