Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology.
Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology.
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DOI：
10.1126/sciadv.abe4601
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发表时间：
2021-05
期刊：
影响因子：
13.6
通讯作者：
Kipnis J
中科院分区：
文献类型：
--
作者：
Da Mesquita S;Herz J;Wall M;Dykstra T;de Lima KA;Norris GT;Dabhi N;Kennedy T;Baker W;Kipnis J
脑膜免疫功能障碍与认知能力下降、胶质细胞受损和阿尔茨海默病病理学增强有关。衰老导致脑膜炎和外周免疫力的进行性恶化，这可能加速认知能力的下降。我们假设，年龄相关的C-C趋化因子受体7型（CCR 7）依赖性免疫细胞通过淋巴管系统的流出减少介导了脑老化的某些方面，并可能加剧认知能力下降和阿尔茨海默病样脑β淀粉样蛋白（Aβ）病理。我们报告了老年小鼠脑膜T细胞CCR 7表达的减少，这与效应和调节性T细胞的增加有关。造血CCR 7缺陷模拟了脑膜T细胞中与衰老相关的变化，并导致胶质淋巴流入减少和认知障碍。5xFAD转基因小鼠中CCR 7的缺失导致有害的神经血管和小胶质细胞活化，沿着脑中Aβ沉积增加。用抗CD 25抗体治疗老年小鼠缓解了恶化的脑膜调节性T细胞反应并改善了认知功能，突出了调节脑膜免疫以微调衰老和神经退行性疾病中的脑功能的治疗潜力。
Dysfunctional meningeal immunity is associated with cognitive decline, impaired glymphatics, and enhanced Alzheimer’s pathology. Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.
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影响因子：
25
作者：
Habib, Naomi;McCabe, Cristin;Medina, Sedi;Varshavsky, Miriam;Kitsberg, Daniel;Dvir-Szternfeld, Raz;Green, Gilad;Dionne, Danielle;Nguyen, Lan;Marshall, Jamie L.;Chen, Fei;Zhang, Feng;Kaplan, Tommy;Regev, Aviv;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
64.8
作者：
Filiano AJ;Xu Y;Tustison NJ;Marsh RL;Baker W;Smirnov I;Overall CC;Gadani SP;Turner SD;Weng Z;Peerzade SN;Chen H;Lee KS;Scott MM;Beenhakker MP;Litvak V;Kipnis J
通讯作者：
Kipnis J
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
脑膜免疫调节学习和记忆：IL-4 的关键作用。
影响因子：
15.3
作者：
Derecki, Noel C.;Cardani, Amber N.;Yang, Chun Hui;Quinnies, Kayla M.;Crihfield, Anastasia;Lynch, Kevin R.;Kipnis, Jonathan
通讯作者：
Kipnis, Jonathan
影响因子：
30.5
作者：
Alves de Lima K;Rustenhoven J;Da Mesquita S;Wall M;Salvador AF;Smirnov I;Martelossi Cebinelli G;Mamuladze T;Baker W;Papadopoulos Z;Lopes MB;Cao WS;Xie XS;Herz J;Kipnis J
通讯作者：
Kipnis J