Influenza vaccination in early Alzheimer's disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells
Influenza vaccination in early Alzheimer's disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells
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早期阿尔茨海默氏病的流感疫苗通过抑制调节性 T 细胞拯救淀粉样变性并改善 APP/PS1 小鼠的认知缺陷
DOI：
10.1186/s12974-020-01741-4
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发表时间：
2020-02-19
影响因子：
9.3
通讯作者：
Yao, Zhibin
中科院分区：
文献类型：
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作者：
Yang, Yunjie;He, Zitian;Yao, Zhibin
背景：阿尔茨海默病（AD）是一种与免疫系统功能失调密切相关的神经退行性疾病。我们之前的研究结果表明，灭活流感疫苗（IIV）促进海马神经发生并阻断脂多糖（LPS）诱导的认知障碍。然而，iv是否能改善AD小鼠模型的认知缺陷仍不清楚。此外，近年来鼓励对阿尔茨海默病进行早期干预。在此，我们研究了在APP/ PS1小鼠模型中，临床前阶段的iv免疫是否会改变AD的脑病理和认知缺陷。方法：采用Morris水迷宫（Morris water maze， MWM）评价空间学习记忆能力。采用免疫组化方法观察脑β -淀粉样蛋白斑块负荷和活化小胶质细胞的变化。此外，流式细胞术分析脾脏中Treg细胞的比例。细胞因子抗体阵列测量细胞因子在大脑和外周免疫系统中的变化。结果：五次iv免疫激活小胶质细胞，减轻A β负担，改善认知功能障碍。同时，IIV诱导的免疫应答通过降低Foxp3（+）调节性T细胞（Treg）活性打破了外周免疫抑制，而使用全反式维甲酸（ATRA）恢复外周Treg水平则减弱了IIV对A β负担和认知功能的保护作用。有趣的是，iv免疫可能会增加APP/PS1小鼠大脑中促炎和抗炎细胞因子的表达，增强小胶质细胞的激活，增强A β的聚集和吞噬，从而在紊乱的免疫微环境中建立新的稳态。结论：总之，我们的研究结果表明，早期多次iv免疫通过打破treg介导的全身免疫耐受，维持小胶质细胞的激活和清除a β斑块，最终改善APP/PS1小鼠的认知缺陷，从而对APP/PS1小鼠产生有益的免疫调节作用。
Background: Alzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model.Methods: We assessed spatial learning and memory using Morris water maze (MWM). The brain beta-amyloid (A beta) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system.Results: Five IIV immunizations activated microglia, reduced the A beta burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3(+) regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on A beta burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of A beta, thereby creating new homeostasis in the disordered immune microenvironment.Conclusions: Altogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of A beta plaques, eventually improving cognitive deficits.