小柯机器人

脑膜淋巴管影响小胶质细胞反应和抗Aβ免疫疗法
2021-04-30 15:47

近日,美国维吉尼亚大学Jonathan Kipnis、Sandro Da Mesquita等研究人员合作发现,脑膜淋巴管影响小胶质细胞反应和抗Aβ免疫疗法。相关论文于2021年4月28日在线发表于国际学术期刊《自然》。

研究人员发现,5xFAD小鼠(表达家族性阿尔茨海默氏病(AD)中发现的五个突变淀粉样蛋白沉积的小鼠模型)中的脑膜淋巴管消融会加剧Aβ的沉积、小胶质细胞增生、神经血管疾病,从而恶化了接受抗Aβ被动免疫疗法治疗小鼠的结局功能障碍和行为缺陷。相比之下,血管内皮生长因子C的治疗性递送改善了单克隆抗体对Aβ的清除。

值得注意的是,脑膜淋巴功能受损的5xFAD小鼠的小胶质细胞的基因标记与AD个体的大脑中激活的小胶质细胞转录谱之间存在很大的重叠。总体而言,这些数据表明,脑膜淋巴引流受损会加重AD中的小胶质细胞炎症反应,而脑膜淋巴功能的增强与免疫疗法的结合可能会导致更好的临床结果。

据介绍,AD是痴呆症最普遍的病因。尽管目前尚无有效的AD治疗方法,但是使用抗淀粉样蛋白β(Aβ)单克隆抗体的被动免疫疗法是一种有前途的治疗策略。脑膜淋巴引流在脑内Aβ的积累中具有重要作用,但尚不清楚脑膜淋巴功能的调节是否会影响AD免疫治疗的结果。

附:英文原文

Title: Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Author: Sandro Da Mesquita, Zachary Papadopoulos, Taitea Dykstra, Logan Brase, Fabiana Geraldo Farias, Morgan Wall, Hong Jiang, Chinnappa Dilip Kodira, Kalil Alves de Lima, Jasmin Herz, Antoine Louveau, Dylan H. Goldman, Andrea Francesca Salvador, Suna Onengut-Gumuscu, Emily Farber, Nisha Dabhi, Tatiana Kennedy, Mary Grace Milam, Wendy Baker, Igor Smirnov, Stephen S. Rich, Bruno A. Benitez, Celeste M. Karch, Richard J. Perrin, Martin Farlow, Jasmeer P. Chhatwal, David M. Holtzman, Carlos Cruchaga, Oscar Harari, Jonathan Kipnis

Issue&Volume: 2021-04-28

Abstract: Alzheimer’s disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.

DOI: 10.1038/s41586-021-03489-0

Source: https://www.nature.com/articles/s41586-021-03489-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0