海马小胶质细胞在5xFAD小鼠抑郁模型早发认知损害中的作用

The effects of hippocampal microglia of 5xFAD mice depression model showing early-onset cognitive impairment

目的:通过慢性社交挫败应激(CSDS)模型建立抑郁状态下早期阿尔茨海默病(AD)小鼠模型,观察海马区小胶质细胞对5xFAD转基因小鼠早发性学习记忆损害的影响。方法:2月龄5xFAD转基因小鼠及对照组C57BL/6J(WT)受CD1小鼠直接攻击与间接威胁共8 d,建立CSDS模型,通过糖水偏好实验、悬尾实验评估模型建立后小鼠抑郁状态,采用条件恐惧测试及Morris水迷宫实验检验小鼠学习记忆变化。免疫荧光染色观察小鼠海马β-淀粉样蛋白(Aβ)沉积、离子钙结合衔接分子1(Iba-1)及离子型谷氨酸受体2(GluA2)的表达。结果:CSDS刺激后5xFAD小鼠糖水偏好性下降(P<0.05),悬尾不动时间增加(P<0.05),WT小鼠CSDS刺激后悬尾不动时间增加(P<0.05),表现出抑郁样行为。认知相关行为学结果发现CSDS刺激的5xFAD小鼠空间学习记忆比5xFAD对照组下降(P<0.05),但WT组小鼠空间学习能力无明显改变。免疫荧光染色结果提示CSDS刺激的5xFAD小鼠海马区Aβ表达显著多于5xFAD小鼠未刺激组(P<0.05),且Iba-1水平升高(P<0.05)。CSDS刺激的5xFAD小鼠海马小胶质细胞中GluA2明显下调(P<0.01),但在CSDS刺激的WT小鼠中显著升高(P<0.05)。结论:5xFAD小鼠抑郁模型提早出现认知退化、海马区小胶质细胞显著活化、Aβ表达升高。CSDS刺激的5xFAD小鼠海马区小胶质细胞GluA2表达下调,提示AD小鼠抑郁状态下提早出现认知损害与小胶质细胞谷氨酸受体改变有关。

Objective:Chronic social defeat stress(CSDS)was used to establish a mouse model of early-stage Alzheimer’s disease(AD)under depression,and to observe the effects of hippocampal microglia on the early-onset of learning and memory impairment in 5 xFAD transgenic mice.Methods:Two-month-old 5 xFAD mice and control C57 BL/6 J(WT)group were directly attacked and indirectly threatened by CD1 mice for a total of 8 d to establish CSDS model.And evaluate mice depression state by sucrose preference test,tail suspension test.Conditioned fear memory and Morris water maze were used to test mice learning and memory changes.The deposition ofβ-amyloid(Aβ),ionized calcium binding adapter molecule-1(Iba-1)and ionic glutamate receptor 2(GluA2)expression level were observed by immunofluorescence staining.Results:CSDS stimulated 5 xFAD group mice showed sucrose preference decreasing(P<0.05)and immobility time increasing(P<0.05)in tail suspension test,WT mice after CSDS stimulated showed immobility time increasing(P<0.05)in tail suspension test,which indicate that mice were depressed.Cognitive related behavior test showed CSDS stimulated 5 xFAD group decreased compared with the 5 xFAD control group(P<0.05).However,the spatial learning ability of WT group did not change significantly(P<0.05).Immunofluorescence staining showed that the expression of Aβin the hippocampus of CSDS stimulated 5 xFAD mice was significantly higher than that of the control group(P<0.05),and the level of activated microglia was increased.GluA2 in activated microglia was significantly down-regulated in CSDS stimulated 5 xFAD(P<0.01),but significantly increased in WT mice CSDS model(P<0.05).Conclusion:The CSDS model of 5 xFAD mice showed early-onset cognitive impairment,significant hippocampal microglia activation and Aβexpression increasing.The microglia GluA2 expression in CSDS stimulated 5 xFAD mice was downregulated,which was significantly different from WT,suggesting that the early cognitive impairment in AD mice under depression was related to the changes of glutamate receptors in microglia.