Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer's disease.
Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer's disease.
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DOI：
10.1073/pnas.2309221120
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发表时间：
2023-09-12
影响因子：
11.1
通讯作者：
Weiner, Howard L.
中科院分区：
文献类型：
--
作者：
Lopes, Juliana R.;Zhang, Xiaoming;Mayrink, Julia;Tatematsu, Bruna K.;Guo, Lydia;LeServe, Danielle S.;Abou-El-Hassan, Hadi;Rong, Felipe;Dalton, Maria J.;Oliveira, Marilia G.;Lanser, Toby B.;Liu, Lei;Butovsky, Oleg;Rezende, Rafael M.;Weiner, Howard L.
阿尔茨海默病（Alzheimer's disease，AD）是一种以淀粉样斑块、神经元缠结和小胶质细胞活化为特征的神经退行性疾病。靶向淀粉样蛋白β的疗法在AD受试者中显示出积极的效果。鼻用抗CD3已被证明可通过诱导抑制脑中小胶质细胞炎症的调节性T细胞来治疗患有进行性形式的实验性自身免疫性脑脊髓炎（多发性硬化症的模型）的动物。在这里，我们表明，鼻抗CD3也改善了AD的小鼠模型中的疾病，通过靶向小胶质细胞激活在大脑中的淀粉样蛋白β沉积的独立。这些研究确定了一种治疗阿尔茨海默病的独特方法，也可以与抗淀粉样蛋白治疗联合使用。新出现的证据表明，神经炎症的失调，特别是小胶质细胞，在阿尔茨海默病（AD）的发病机制中起着重要作用。包括死亡神经元、营养不良轴突、磷酸化tau蛋白和淀粉样蛋白斑块在内的危险信号将小胶质细胞的功能表型从稳态（M0）改变为神经退行性或疾病相关表型，这反过来驱动神经炎症并促进疾病。因此，靶向小胶质细胞活化的疗法构成了治疗AD的独特方法。在这里，我们报告说，鼻腔给药的抗CD3单克隆抗体在3xTg AD小鼠模型减少小胶质细胞活化和改善认知淀粉样蛋白β沉积无关。此外，基因表达分析表明经鼻抗CD3处理的动物的海马和皮质中的氧化应激降低、轴突发生和突触组织增加以及代谢变化。鼻用抗CD3抗体的有益作用与T细胞在大脑中的积累有关，在大脑中T细胞与小胶质细胞密切接触。综上所述，我们的研究结果确定鼻抗CD3作为一种独特的免疫疗法，以治疗阿尔茨海默病独立于淀粉样蛋白β靶向。
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques, neurofibrillary tangles, and microglial activation. Therapies targeting amyloid beta have shown positive effects in subjects with AD. Nasal anti-CD3 has been shown to treat animals with a progressive form of experimental autoimmune encephalomyelitis, a model for multiple sclerosis, by inducing regulatory T cells that dampen microglial inflammation in the brain. Here, we show that nasal anti-CD3 also ameliorates disease in a murine model of AD by targeting microglial activation in the brain independent of amyloid beta deposition. These studies identify a unique approach to treat Alzheimer’s disease that could also be given in combination with antiamyloid therapy. Emerging evidence suggests that dysregulation of neuroinflammation, particularly that orchestrated by microglia, plays a significant role in the pathogenesis of Alzheimer’s disease (AD). Danger signals including dead neurons, dystrophic axons, phosphorylated tau, and amyloid plaques alter the functional phenotype of microglia from a homeostatic (M0) to a neurodegenerative or disease-associated phenotype, which in turn drives neuroinflammation and promotes disease. Thus, therapies that target microglia activation constitute a unique approach for treating AD. Here, we report that nasally administered anti-CD3 monoclonal antibody in the 3xTg AD mouse model reduced microglial activation and improved cognition independent of amyloid beta deposition. In addition, gene expression analysis demonstrated decreased oxidative stress, increased axogenesis and synaptic organization, and metabolic changes in the hippocampus and cortex of nasal anti-CD3 treated animals. The beneficial effect of nasal anti-CD3 was associated with the accumulation of T cells in the brain where they were in close contact with microglial cells. Taken together, our findings identify nasal anti-CD3 as a unique form of immunotherapy to treat Alzheimer’s disease independent of amyloid beta targeting.
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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
DOI：
10.1093/brain/aww113
发表时间：
2016-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Mayo L;Cunha AP;Madi A;Beynon V;Yang Z;Alvarez JI;Prat A;Sobel RA;Kobzik L;Lassmann H;Quintana FJ;Weiner HL
通讯作者：
Weiner HL
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
--
作者：
Baek H;Ye M;Kang GH;Lee C;Lee G;Choi DB;Jung J;Kim H;Lee S;Kim JS;Lee HJ;Shim I;Lee JH;Bae H
通讯作者：
Bae H
影响因子：
29
作者：
Manly, Jennifer J.;Jones, Richard N.;Weir, David
通讯作者：
Weir, David