有氧运动抑制神经炎症减轻阿尔茨海默病模型小鼠认知障碍

Aerobic exercise inhibits neuroinflammation and alleviates cognitive impairment in Alzheimer’s disease model mice

背景:阿尔茨海默病患者主要表现为认知和记忆功能障碍,有氧运动能够抑制内质网应激,改善阿尔茨海默病患者认知功能,然而有氧运动是否抑制内质网应激依赖的神经炎症尚不清楚。目的:探究有氧运动对阿尔茨海默病模型小鼠神经炎症和认知障碍的影响。方法:C57BL/6J野生型雄性小鼠50只随机分为野生对照组、野生运动组;APP/PS1双转基因雄性小鼠50只随机分为阿尔茨海默病组和阿尔茨海默病运动组,每组各25只。野生运动组、阿尔茨海默病运动组小鼠进行有氧运动训练(跑台运动,45 min/d,速度为12 m/min,5 d/周,共8周);将野生对照组、阿尔茨海默病组小鼠放置在安静跑台上。Morris水迷宫实验检测小鼠认知能力;硫黄素-S染色检测海马组织β-淀粉样蛋白含量;苏木精-伊红染色和尼氏染色检测小鼠海马组织损伤情况;免疫组化染色检测海马组织β-淀粉样蛋白、p-Tau水平;免疫荧光染色检测海马组织神经炎症相关因子阳性细胞数;Western Blot检测海马组织内质网应激相关蛋白p-IRE1、IRE1、p-PERK、PERK、ATF6、GRP78、Bip、Caspase-12、Iba-1、GFAP的水平。结果与结论:①与野生对照组相比,阿尔茨海默病组小鼠逃避潜伏期增加、到达先前平台的次数和在平台停留的时间减少,海马组织β-淀粉样蛋白、Tau水平和内质网应激相关蛋白p-IRE1/IRE1、p-PERK/PERK、ATF6、GRP78、Bip、Caspase-12、Iba-1、GFAP水平升高,神经炎症相关因子Iba-1^(+)、Iba-1^(+)TNF-α^(+)、Iba-1^(+)IL-6^(+)、Iba-1^(+)IL-1β^(+)、GFAP^(+)、GFAP^(+)TNF-α^(+)、GFAP^(+)IL-6^(+)、GFAP^(+)IL-1β^(+)阳性细胞数增加,Iba-1^(+)IL-4^(+)、Iba-1^(+)IL-10^(+)、GFAP^(+)IL-4^(+)、GFAP^(+)IL-10^(+)阳性细胞数减少(P<0.05);与阿尔茨海默病组相比,阿尔茨海默病运动组小鼠逃避潜伏期减少、到达先前平台的次数和在平台停留的时间增加,海马组织β-淀粉样蛋白、Tau水平和内质网应激相关蛋白水平及炎症相关因子阳性细胞数呈现相反的变化(P<0.05)。②结果说明,有氧运动能够抑制海马组织内质网应激依赖的神经炎症,减轻阿尔茨海默病小鼠认知障碍。

BACKGROUND:Patients with Alzheimer’s disease mainly show cognitive and memory dysfunctions.Aerobic exercise can inhibit endoplasmic reticulum stress and improve cognitive function of the patients.However,whether aerobic exercise can inhibit endoplasmic reticulum stress dependent neuroinflammation is still unclear.OBJECTIVE:To explore the effect of aerobic exercise on neuroinflammation and cognitive impairment in a mouse model of Alzheimer’s disease.METHODS:Fifty C57BL/6J wild-type male mouse mice were randomly divided into wild-type control and wild-type exercise groups,while another 50 APP/PS1 double transgenic male mice were randomly divided into Alzheimer’s disease group and Alzheimer's disease exercise group,with 25 mice in each group.Mice in the wild-type exercise and Alzheimer's disease exercise groups received aerobic exercise training(treadmill training,45 min/d,12 m/min,5 d/wk,8 weeks in total).Mice in the wild-type control and Alzheimer’s disease groups were placed on the quiet running platform.Morris water maze test was used to detect the cognitive ability of mice.Hematoxylin-eosin staining and Nissl staining were used to detect hippocampal tissue damage in mice.Thioflavin-S staining was used to detectβ-amyloid content in hippocampal tissue.Immunohistochemistry was used to detectβ-amyloid and p-Tau levels in hippocampal tissue.Immunofluorescence staining was used to detect the number of positive cells for neuroinflammation-related factors in hippocampal tissue.Western blot was used to detect p-IRE1,IRE1,p-PERK,PERK,ATF6,GRP78,Bip,Caspase-12,Iba-1,and GFAP protein levels.RESULTS AND CONCLUSION:Compared with the wild-type control group,escape latency was increased,the number of times they reached the previous platform and the time they stayed on the platform were decreased,β-amyloid and Tau levels,p-IRE1/IRE1,p-PERK/PERK,ATF6,GRP78,Bip,Caspase-12,Iba-1,and GFAP protein levels,Iba-1^(+),Iba-1^(+)TNF-α^(+),Iba-1^(+)IL-6^(+),Iba-1^(+)IL-1β^(+),GFAP^(+),GFAP^(+)TNF-α^(+),GFAP^(+)IL-6^(+),GFAP^(+)IL-1β^(+)positive cells in hippocampal tissue were increased,and Iba-1^(+)IL-4^(+),Iba-1^(+)IL-10^(+),GFAP^(+)IL-4^(+),GFAP^(+)IL-10^(+)positive cells were decreased in the Alzheimer’s disease group(P<0.05).Compared with Alzheimer’s disease group,escape latency was decreased,the number of times they reached the previous platform and the time they stayed on the platform were increased,β-amyloid and Tau levels,p-IRE1/IRE1,p-PERK/PERK,ATF6,GRP78,Bip,Caspase-12,Iba-1,GFAP protein levels,Iba-1^(+),Iba-1^(+)TNF-α^(+),Iba-1^(+)IL-6^(+),Iba-1^(+)IL-1β^(+),GFAP^(+),GFAP^(+)TNF-α^(+),GFAP^(+)IL-6^(+),and GFAP^(+)IL-1β^(+)positive cells in hippocampal tissue were decreased,and Iba-1^(+)IL-4^(+),Iba-1^(+)IL-10^(+),GFAP^(+)IL-4^(+),GFAP^(+)IL-10^(+)positive cells were increased in the Alzheimer’s disease exercise group(P<0.05).To conclude,aerobic exercise can reduce cognitive impairment in Alzheimer’s disease mice by inhibiting endoplasmic reticulum stress and neuroinflammation in hippocampal tissue.