n-3 polyunsaturated fatty acids ameliorate learning and memory abilities in APPPS1 mice by regulating microglial activation and polarization

Mengyan DENG; Xiaohui ZHU; Li HUANG; Qian BAI; Weifang LI; Bin WANG; Mantian MI

doi:10.16016/j.2097-0927.202309156

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n-3 polyunsaturated fatty acids ameliorate learning and memory abilities in APPPS1 mice by regulating microglial activation and polarization

Public Health and Preventive Medicine | 更新时间：2026-01-09

- n-3 polyunsaturated fatty acids ameliorate learning and memory abilities in APPPS1 mice by regulating microglial activation and polarization
- Journal of Army Medical University Vol. 46, Issue 9, Pages: 928-939(2024)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)军事预防医学系营养与食品安全研究中心，重庆市医学营养研究中心，营养与健康重庆市重点实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81773410)
- DOI：10.16016/j.2097-0927.202309156
  CLC： R322.81;R338.64;R977.6
- Received：28 September 2023，
  
  Revised：2023-12-28，
  
  Published：15 May 2024
- 稿件说明：
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Mengyan DENG, Xiaohui ZHU, Li HUANG, et al. n-3 polyunsaturated fatty acids ameliorate learning and memory abilities in APPPS1 mice by regulating microglial activation and polarization[J]. Journal of Army Medical University, 2024, 46(9): 928-939.
DOI：

Mengyan DENG, Xiaohui ZHU, Li HUANG, et al. n-3 polyunsaturated fatty acids ameliorate learning and memory abilities in APPPS1 mice by regulating microglial activation and polarization[J]. Journal of Army Medical University, 2024, 46(9): 928-939. DOI： 10.16016/j.2097-0927.202309156.

摘要

目的

建立Fat-1/APPPS1转基因小鼠的体内模型及小胶质细胞体外模型，探讨n-3多不饱和脂肪酸(n-3 polyunsaturated fatty acids，n-3 PUFAs)调节小胶质细胞激活及极化改善APPPS1小鼠学习记忆能力的效果和机制。

方法

将杂合子Fat-1雄性小鼠与杂合子APPPS1雌性小鼠进行杂交，筛选子代得到WT、Fat-1、Fat-1/APPPS1以及APPPS1雄性小鼠，培育至9月龄。运用Morris水迷宫实验评估小鼠的学习记忆能力；气-质联用技术(GS-MS)测定小鼠脑组织内多不饱和脂肪酸水平；运用免疫组织化学法检测小鼠大脑海马区β淀粉样蛋白(β-amyloid protein

Aβ)沉积情况；运用组织免疫荧光、qRT-PCR及酶联免疫吸附实验检测各组小鼠中枢神经系统(central nervous system

CNS)炎症水平，小胶质细胞激活及极化水平，基因

Iba

-1的转录及表达小胶质细胞激活水平，基因

86、

206的转录及表达小胶质细胞极化水平。采用脂多糖(LPS)诱导小鼠来源的永生化BV2小胶质细胞损伤建立细胞炎症模型，用二十二碳六烯酸(docosahexaenoic acid

DHA)和二十碳五烯酸(eicosapentaenoic acid

EPA)对细胞预处理，运用细胞免疫荧光、qRT-PCR和蛋白免疫印迹技术检测各组小胶质细胞炎症、激活及极化水平，采用的激活与极化指标与动物实验相同。

结果

与APPPS1小鼠相比，内源性表达n-3 PUFAs的Fat-1/APPPS1小鼠学习记忆障碍明显改善(

＜0.05)，海马区Aβ沉积有效缓解(

＜0.05)，CNS炎症水平以及小胶质细胞激活水平显著降低(

＜0.05)，同时小胶质细胞激活表型从M1向M2型转化(

＜0.05)。DHA+EPA预处理显著降低了LPS诱导的BV2细胞炎症水平(

＜0.05)，且促使细胞从M1向M2型转化(

＜0.05)。

结论

n-3 PUFAs可以抑制APPPS1小鼠大脑小胶质细胞激活，调节小胶质细胞由M1向M2转化，降低中枢神经炎症水平，改善APPPS1小鼠学习记忆障碍。

Abstract

Objective

To construct a model of Fat-1/APPPS1 transgenic mice and a cellular model of microglia and explore the improvement effect and underlying mechanism of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the learning and memory abilities of APPPS1 mice by regulating microglial activation and polarization.

Methods

After the male mice with heterozygous Fat-1 genotype were mated with the female ones with heterozygous APPPS1 genotype

genetic identification was used to screen the male offspring with Fat-1/APPPS1 genotype. Then after the male wild-type (WT) mice and those with Fat-1

Fat-1/APPPS1

and APPPS1 genotypes were bred until 9 months old

their learning and memory abilities were evaluated with Morris water maze (MWM) test. In addition

gas chromatography-mass spectrometry (GC-MS) was performed to detect the concentration of PUFAs in the brain

and immunohistochemistry (IHC) was applied to detect the deposition of β-amyloid protein (Aβ) in the hippocampal regions. Moreover

immunofluorescence assay

qRT-PCR

and enzyme-linked immunosorbent assays (ELISA) were conducted to measure inflammation

and transcription and expression of Iba-1 (indicating the microglial activation) and CD86 and CD206 (indicating microglial polarization) in central nervous system (CNS). After pretreated with DHA+EPA (25 μmol/mL ∶25 μmol/mL)

microglial model of inflammatory injury was established in immortalized mouse BV2 cells induced by LPS (1 μg/mL). Afterwards

immunofluorescence assay

qRT-PCR and Western blotting were used to detect inflammation and microglial activation and polarization.

Results

Compared with the APPPS1 mice

endogenous n-3 PUFAs effectively improved the learning and memory disorders in Fat-1/APPPS1 ones (

0.05)

remarkably alleviated Aβ deposition in the hippocampal regions (

0.05)

evidently reduced CNS inflammation and microglial activation (

0.05) and transformed the activated microglia from M1 to M2 (

0.05). Furthermore

BV2 cells with DHA+EPA pretreatment obviously resisted LPS-induced cellular inflammation and induced activated ones from M1 to M2 (

0.05).

Conclusion

n-3 PUFAs inhibit the microglial activation

regulate the microglial polarization from M1 to M2

reduce CNS inflammation

and thus alleviate learning and memory disorders in APPPS1 mice.

关键词

Keywords

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