TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.
TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.
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DOI：
10.15252/emmm.201606370
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发表时间：
2016-09
影响因子：
11.1
通讯作者：
Haass C
中科院分区：
文献类型：
--
作者：
Xiang X;Werner G;Bohrmann B;Liesz A;Mazaheri F;Capell A;Feederle R;Knuesel I;Kleinberger G;Haass C
免疫治疗方法是目前治疗阿尔茨海默病（AD）最先进的方法。抗淀粉样蛋白β肽（Aβ）抗体与淀粉样斑块结合，并通过Fc受体介导的吞噬作用诱导其被小胶质细胞清除。小胶质细胞功能障碍可能在阿尔茨海默病的发病机制中起关键作用，并可能导致抗体介导的a β清除效果降低。最近，髓样细胞2 （TREM2）上表达的触发受体杂合突变（一种参与吞噬的小胶质基因）与晚发性阿尔茨海默病有遗传联系。TREM2的缺失降低了小胶质细胞吞噬Aβ的能力。我们现在已经研究了TREM2的缺失是否会影响免疫治疗方法的疗效。我们发现抗a β抗体在TREM2存在或不存在的情况下以剂量依赖的方式刺激a β摄取和淀粉样斑块清除。然而，TREM2缺失的N9小胶质细胞系、巨噬细胞和原代小胶质细胞对抗体结合的a β的摄取明显减少，因此淀粉样斑块的清除减少。滴定实验显示，tre2敲除细胞清除淀粉样斑块效果的降低可以通过提高治疗性抗体的浓度来补偿。
Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β‐peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor‐mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody‐mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD. Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti‐Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose‐dependent manner in the presence or absence of TREM2. However, TREM2‐deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody‐bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies.
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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：
14.5
作者：
Lathuiliere, Aurelien;Laversenne, Vanessa;Aebischer, Patrick
通讯作者：
Aebischer, Patrick
影响因子：
4
作者：
Bohrmann, Bernd;Baumann, Karlheinz;Loetscher, Hansruedi
通讯作者：
Loetscher, Hansruedi
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：
2.7
作者：
Paradowska-Gorycka, Agnieszka;Jurkowska, Monika
通讯作者：
Jurkowska, Monika