TREM2 and the neuroimmunology of Alzheimer's disease.
TREM2 and the neuroimmunology of Alzheimer's disease.
复制标题
DOI：
10.1016/j.bcp.2013.11.021
复制
发表时间：
2014-04-15
影响因子：
5.8
通讯作者：
El Khoury, Joseph
中科院分区：
文献类型：
--
作者：
Hickman, Suzanne E.;El Khoury, Joseph
晚发性阿尔茨海默病 (AD) 是一种散发性疾病，随着年龄的增长患病率不断增加。载脂蛋白 E (ApoEε4) 的 ε4 等位基因是唯一已知的迟发性 AD 的主要危险因素。最近，两组研究人员独立鉴定了 TREM2 基因的变体，该基因编码在骨髓细胞 2 上表达的触发受体，导致迟发性 AD 的易感性增加，其比值比与 ApoEε4 相似。 TREM2 是先天免疫细胞上表达的受体。使用一种称为直接 RNA 测序的新技术，我们确定了小胶质细胞（主要的先天神经免疫细胞）的定量转录组，并证实 TREM2 是中枢神经系统中主要的小胶质细胞特异性基因。在过去的几年里，我们已经证明小胶质细胞在 AD 中发挥着双重作用。小胶质细胞可以保护并促进 Aβ 的吞噬、降解和最终清除，Aβ 是沉积在阿尔茨海默病患者大脑中的致病蛋白。然而，随着疾病进展，小胶质细胞功能失调，释放神经毒素，失去清除 Aβ 的能力，并产生促炎细胞因子，促进 Aβ 产生和积累。 TREM2 已被证明可以调节骨髓细胞的吞噬能力及其炎症反应。在这里，我们提出 TREM2 变异导致阿尔茨海默氏病的机制是通过下调小胶质细胞的 Aβ 吞噬能力和调节这些细胞的促炎反应。根据我们的讨论，我们提出 TREM2 是阻止或延迟 AD 进展的潜在治疗靶点。
Late-onset Alzheimer’s disease (AD) is a sporadic disorder with increasing prevalence in aging. The ε4 allele of Apolipoprotein E(ApoEε4) was the only known major risk factor for late onset AD. Recently, two groups of investigators independently identified variants of the TREM2 gene, encoding triggering receptor expressed on myeloid cells 2 as causing increased susceptibility to late onset AD with an odds ratio similar to that of ApoEε4. TREM2 is a receptor expressed on innate immune cells. Using a novel technology called Direct RNA Sequencing wedetermined the quantitative transcriptome of microglia, the principal innate neuroimmune cells and confirmed that TREM2 is a major microglia-specific gene in the central nervous system. Over the past several years we have shown that microglia play a dichotomous role in AD. Microglia can be protective and promote phagocytosis, degradation and ultimately clearance of Aβ, the pathogenic protein deposited in the brains of Alzheimer’s patients. However, with disease progression, microglia become dysfunctional, release neurotoxins, lose their ability to clear Aβ and produce pro-inflammatory cytokines that promote Aβ production and accumulation. TREM2 has been shown to regulate the phagocytic ability of myeloid cells and their inflammatory response. Here we propose that the mechanism(s) by which TREM2 variants cause Alzheimer’s disease are via down regulation of the Aβ phagocytic ability of microglia and by dysregulation of the pro-inflammatory response of these cells. Based on our discussion we propose that TREM2 is a potential therapeutic target for stopping ordelaying progression of AD.
登录
查看更多内容
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
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
CD36介导了对β-淀粉样蛋白的先天宿主反应。
影响因子：
15.3
作者：
El Khoury, JB;Moore, KJ;Means, TK;Leung, J;Terada, K;Toft, M;Freeman, MW;Luster, AD
通讯作者：
Luster, AD
影响因子：
11.2
作者：
Frenkel, Dan;Puckett, Lindsay;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.