Immunization with Bacillus Calmette-Guerin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain
Immunization with Bacillus Calmette-Guerin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain
复制标题
卡介苗 (BCG) 免疫可通过向大脑招募消炎单核细胞来缓解 APP/PS1 小鼠的神经炎症和认知缺陷
DOI：
10.1016/j.nbd.2017.02.001
复制
发表时间：
2017
影响因子：
6.1
通讯作者：
Yao Zhi Bin
中科院分区：
文献类型：
--
作者：
Zuo Zejie;Qi Fangfang;Yang Junhua;Wang Xiao;Wu Yingying;Wen Yaru;Yuan Qunfang;Zou Juntao;Guo Kaihua;Yao Zhi Bin
免疫系统在阿尔茨海默病(AD)的发展过程中起着至关重要的作用。最近，由全身免疫激活诱导的免疫依赖级联反应已被证实在AD小鼠模型中发挥有益的作用。本实验以4Aβ1-15疫苗为阳性对照，检测卡介苗免疫对APP/PS1AD模型小鼠的AD病理和认知功能的影响。研究发现，卡介苗治疗可以逆转4Aβ1-15组大鼠的认知功能下降，但并不能减轻脑内A-淀粉样蛋白(β-β，A-A)的负荷。然后，我们证明了在卡介苗免疫的APP/PS1小鼠中，跨越脉络丛和血管周围间隙的炎症溶解单核细胞增强了对斑块病理脑部位的募集。此外，对照APP/PS1小鼠升高的脾细胞Foxp3+调节性T细胞水平通过卡介苗治疗而不是4Aβ1-15疫苗被下调至野生型(WT)水平。此外，卡介苗处理组比对照组和4Aγ1-15疫苗组产生更多的循环干扰素-β。尽管与对照组相比，卡介苗和4Aβ1-15组小鼠脑内促炎细胞因子水平也有相似的降低，但只有卡介苗在上调APP/PS1小鼠脑内抗炎细胞因子水平和上调脑内神经营养因子的表达方面具有显著作用。提示卡介苗通过减轻全身免疫抑制、诱导干扰素-γ应答和减轻神经炎性反应，对APP/PS1小鼠具有良好的免疫调节作用。
The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aβ1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aβ1-15 group, but did not reduce the β-amyloid (Aβ) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aβ1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aβ1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aβ1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.