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 β-amyloid (Aβ) 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 Aβ 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 Aβ 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 Aβ, 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 Aβ plaques, eventually improving cognitive deficits.

中文翻译：

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早期阿尔茨海默氏病的流感疫苗可以通过抑制调节性T细胞来拯救淀粉样变性病并改善APP / PS1小鼠的认知功能障碍。

背景技术阿尔茨海默氏病（AD）是与免疫系统功能异常密切相关的神经退行性疾病。我们以前的结果表明灭活的流感疫苗（IIV）促进海马神经发生并阻止脂多糖（LPS）引起的认知障碍。但是，IIV是否可以改善AD小鼠模型中的认知缺陷尚不清楚。此外，近年来鼓励对AD进行早期干预。在这里，我们调查了在AD的临床前阶段进行IIV免疫是否会改变APP / PS1小鼠模型的脑部病理和认知功能障碍。方法我们使用莫里斯水迷宫（MWM）评估了空间学习和记忆能力。通过免疫组织化学研究脑β-淀粉样蛋白（Aβ）斑块负荷和活化的小胶质细胞。此外，流式细胞仪用于分析脾脏中Treg细胞的比例。进行了细胞因子抗体阵列测量，以测量大脑和外周免疫系统中细胞因子的变化。结果五次IIV免疫激活了小胶质细胞，减轻了Aβ负担并改善了认知障碍。同时，IIV诱导的免疫反应通过降低Foxp3 +调节性T细胞（Treg）活性破坏了外周免疫抑制，而使用全反式维甲酸（ATRA）恢复外周Treg水平减弱了IIV对Aβ负荷和认知功能。有趣的是，IIV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，增强小胶质细胞的活化，并增强Aβ的聚集和吞噬作用，从而在无序的免疫微环境中产生新的体内平衡。结论总之，我们的结果表明，早期的多次IIV免疫通过破坏Treg介导的全身免疫耐受，维持小胶质细胞的活化和去除Aβ斑块，从而在APP / PS1小鼠中发挥有益的免疫调节作用，最终改善了认知缺陷。