Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-Sen University, #74, Zhongshan No. 2 Road, Guangzhou, 510080, China.
Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, #74, Zhongshan No. 2 Road, Guangzhou, 510080, China.
J Neuroinflammation. 2020 Feb 19;17(1):65. doi: 10.1186/s12974-020-01741-4.
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.
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.
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.
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.
阿尔茨海默病（AD）是一种与功能失调的免疫系统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）可促进海马神经发生并阻断脂多糖（LPS）诱导的认知障碍。然而，IIV 是否能改善 AD 小鼠模型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，我们研究了在 AD 的临床前阶段进行 IIV 免疫接种是否会改变 APP/PS1 小鼠模型的大脑病理学和认知缺陷。
我们使用 Morris 水迷宫（MWM）评估空间学习和记忆。通过免疫组织化学检测大脑β-淀粉样蛋白（Aβ）斑块负担和激活的小胶质细胞。此外，使用流式细胞术分析脾脏中 Treg 细胞的比例。进行细胞因子抗体阵列以测量大脑和外周免疫系统中细胞因子的变化。
五次 IIV 免疫接种激活了小胶质细胞，减少了 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）活性打破了外周免疫抑制，而使用全反式视黄酸（ATRA）恢复外周 Treg 水平则削弱了 IIV 对 Aβ 负担和认知功能的保护作用。有趣的是，IIV 免疫接种可能会增加 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，并增强 Aβ 的聚集和吞噬作用，从而在失调的免疫微环境中创造新的平衡。
总的来说，我们的研究结果表明，早期多次进行 IIV 免疫接种通过打破 Treg 介导的全身免疫耐受，维持小胶质细胞的激活和 Aβ 斑块的清除，对 APP/PS1 小鼠产生有益的免疫调节作用，最终改善认知缺陷。
