α-半乳糖神经酰胺(α-Galcer)调节脑内炎症微环境改善Aβ1–42模型小鼠学习记忆功能的机制研究

doi:10.5246/jcps.2024.12.080

中国药学(英文版) ›› 2024, Vol. 33 ›› Issue (12): 1110-1117.DOI: 10.5246/jcps.2024.12.080

α-半乳糖神经酰胺(α-Galcer)调节脑内炎症微环境改善Aβ1–42模型小鼠学习记忆功能的机制研究

景光婵²^,^#, 康静婷¹^,^#, 纪超¹^,^*()

^1. 中国医学科学院基础医学研究所北京协和医学院基础学院基础医学国家级实验教学示范中心, 北京 100005
^2. 中国医学科学院北京协和医院中医科, 北京 100730

收稿日期:2024-07-23 修回日期:2024-08-15 接受日期:2024-09-28 出版日期:2025-01-07 发布日期:2025-01-06
通讯作者: 纪超

α-Galactosylceramide modulates the brain’s inflammatory microenvironment to counteract learning and memory dysfunction in Aβ1–42 model mice

Guangchan Jing²^,^#, Jingting Kang¹^,^#, Chao Ji¹^,^*()

¹ National Demonstration Center for Experimental Basic Medical Education (Peking Union Medical College), Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
² Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China

Received:2024-07-23 Revised:2024-08-15 Accepted:2024-09-28 Online:2025-01-07 Published:2025-01-06
Contact: Chao Ji
About author:
^# Guangchan Jing and Jingting Kang contributed equally to this work.
Supported by:
National Natural Science Foundation of China (Grant No. 81100801).

摘要/Abstract

摘要：

阿尔茨海默病(Alzheimer’s disease, AD)是老年人群中最常见的神经退行性疾病。β-淀粉样蛋白(amyloid-β, Aβ)聚集诱导的神经炎症被认为是AD病理机制的关键因素。据报道, 选择性激活的(M2)巨噬细胞/小胶质细胞可以及时终止神经炎症, 从而在神经退行性疾病中发挥神经保护作用。本研究探讨了α-Galcer对AD模型小鼠学习记忆功能的改善作用及其机制。实验结果显示α-Galcer给药后诱导干扰素调节因子(IRF)5/IRF4的比值降低, 从而促进M2型小胶质细胞比例增加。α-Galcer的这些作用主要是通过影响AD模型小鼠脑内炎症相关细胞因子的表达, 从而诱导神经炎症反应的适时终止, 最终发挥认知功能的改善作用。

关键词: 阿尔茨海默氏病, α-半乳糖神经酰胺, M2型小胶质细胞/巨噬细胞, 神经炎症, 小胶质细胞极化

Abstract:

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder affecting the elderly. Among its pathological mechanisms, neuroinflammation triggered by amyloid-β (Aβ) aggregation is considered a key contributor. Alternatively activated (M2) macrophages and microglia have been shown to play a pivotal role in curbing neuroinflammation, thereby offering neuroprotective effects in neurodegenerative diseases. In the present study, we explored the therapeutic potential of α-galactosylceramide (α-Galcer) in enhancing learning and memory functions in AD model mice while delving into its underlying mechanisms. Our findings demonstrated that α-Galcer administration lowered the interferon regulatory factor (IRF)5/IRF4 ratio, leading to a higher proportion of M2 microglia and macrophages. These beneficial effects were achieved by modulating the expression of inflammation-related cytokines in the brains of AD model mice, thereby accelerating the resolution of neuroinflammation and ultimately enhancing cognitive performance.

Key words: Alzheimer’s disease, α-Galcer, M2 microglia/macrophage, Neuroinflammation, Microglial polarization

Supporting:

景光婵, 康静婷, 纪超. α-半乳糖神经酰胺(α-Galcer)调节脑内炎症微环境改善Aβ1–42模型小鼠学习记忆功能的机制研究[J]. 中国药学(英文版), 2024, 33(12): 1110-1117.

Guangchan Jing, Jingting Kang, Chao Ji. α-Galactosylceramide modulates the brain’s inflammatory microenvironment to counteract learning and memory dysfunction in Aβ1–42 model mice[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(12): 1110-1117.

图/表 6

Figure 1. Effects of α-Galcer on escape latency to the platform of MWM in Aβ1–42-induced memory deficits mice. The trials were set once a day for three consecutive days. Data were expressed as mean ± SE (n = 16, *P < 0.05 vs. sham, #P < 0.05 vs. model).

Figure 2. Effects of α-Galcer on Y maze analysis in Aβ1–42-induced memory deficits mice. The orders of mice entered each arm were recorded during the trials. Data were expressed as mean ± SE. (n = 16, *P < 0.05 vs. sham, #P < 0.05 vs. model).

Figure 3. Effects of α-Galcer on the number of endogenous M2 macrophages in Aβ1–42-induced memory deficits mice by flow cytometry analysis. Cells were obtained from the meninges immediately after the mice were sacrificed. Data were expressed as mean ± SE (n = 5, *P < 0.05 vs. sham group, #P < 0.05 vs. model).

Figure 4. α-Galcer affects the concentration of cortical IL-4 (A) and TNF-α (B) in Aβ1–42-induced memory deficits mice. Data were expressed as mean ± SE (n = 9 in each group, *P < 0.05, **P < 0.01 vs. sham group, #P < 0.05 vs. model group).

Figure 5. Effects of α-Galcer on Aβ1–42-induced IRF4 and IRF5 expression changes in the cortex of each group. (A) IRF4 expression in the cortex of each group was detected by Western blotting analysis. The relative intensity was normalized to β-actin. (B) IRF5 expression in the cortex of each group was detected by Western blotting analysis. The relative intensity was normalized to β-actin. (C) The average ratio of IRF5 to IRF4 (IRF5/IRF4) in each group. All the values represented as mean ± SE (n = 4 in each group, *P < 0.05 vs. sham group, #P < 0.05 vs. model group).

Figure 6. The mechanism of α-Galcer regulating IRF5/IRF4 ratio and thereby enhancing M2 macrophage/microglia to improve learning and memory function in AD mice.

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α-半乳糖神经酰胺(α-Galcer)调节脑内炎症微环境改善Aβ1–42模型小鼠学习记忆功能的机制研究

α-Galactosylceramide modulates the brain’s inflammatory microenvironment to counteract learning and memory dysfunction in Aβ1–42 model mice

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