Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer's disease models.
Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer's disease models.
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DOI：
10.1186/s12974-020-01980-5
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发表时间：
2021-01-09
影响因子：
9.3
通讯作者：
George J
中科院分区：
文献类型：
--
作者：
Fassler M;Rappaport MS;Cuño CB;George J
在髓系细胞中表达的触发受体(TREM2)的遗传变异和突变与早发和晚发性阿尔茨海默病(AD)相关。我们开发了一组单抗，其精选的前导被热切地显示与人和小鼠TREM2的胞外区结合。通过结合膜结合的TREM2，所选择的抗体被证明促进了细胞的增殖，摄取了寡聚的β淀粉样蛋白/凋亡神经元，并以Syk和Akt依赖的方式激活。该抗体可与AD患者脑脊液中的可溶性TREM2结合，并可钝化其脑内注射所驱动的促炎程序。体内治疗后，该抗体被证明可以改善实验性淀粉样变性模型的认知功能，并促进斑块相关小胶质细胞的覆盖和激活。因此，我们描述了一种新的针对膜结合和可溶性TREM2的单抗，它通过诱导小胶质细胞激活和减轻慢性神经炎来改善认知功能。
Genetic variants and mutations in triggering receptor expressed in myeloid cells (TREM2) are associated with premature and late onset Alzheimer’s disease (AD). We developed a panel of monoclonal antibodies, the selected lead of which was avidly shown to bind the extracellular domain of human and murine TREM2. By engaging membrane-bound TREM2, the selected antibody was shown to promote their cellular proliferation, uptake of oligomeric beta amyloid/apoptotic neurons, and activation in a Syk and Akt dependent manner. The antibody was shown to avidly bind soluble TREM2 in the CSF from AD patients and blunted the proinflammatory program driven by its intracerebral injection. Upon in vivo treatment, the antibody was shown to improve cognitive function in experimental amyloidopathy models and to facilitate plaque-associated microglial coverage and activation. Thus, we describe a novel monoclonal antibody targeting membrane bound and soluble TREM2, that improves cognitive function by inducing microglial activation and attenuating chronic neuroinflammation.
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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：
4.4
作者：
Turnbull, Isaiah R.;Gilfillan, Susan;Colonna, Marco
通讯作者：
Colonna, Marco
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：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.
影响因子：
8.8
作者：
Matarin, Mar;Salih, Dervis A.;Edwards, Frances A.
通讯作者：
Edwards, Frances A.