有氧运动通过增强PI3K/Akt信号通路活性抑制阿尔茨海默症小鼠大脑皮质和海马组织老年斑的形成
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摘要
目的:利用PI3K/Akt信号通路特异性抑制剂GNE-317,探讨有氧运动是否通过增强PI3K/Akt信号通路活性抑制APP/PS1小鼠大脑皮质和海马组织中老年斑的形成,为阐明有氧运动防治阿尔茨海默症提供一定的理论依据。方法:雄性APP/PS1小鼠随机分为安静组(SE)、运动组(EX)、GNE-317处理安静组(SEG)和GNE-317处理运动组(EXG)。EX和EXG组小鼠进行为期8周的跑台训练,同时SEG和EXG组小鼠给予GNE-317处理8周。在第9周进行Morris水迷宫实验检测小鼠的认知能力。水迷宫实验结束后,分离所有小鼠的大脑皮质和海马组织。通过免疫组化实验观察各组小鼠大脑皮质和海马组织老年斑的数量;通过Western blot检测APP、Aβ42及BACE1的蛋白表达水平。结果:8周跑台训练后,EX组小鼠与SE组小鼠相比,大脑皮质和海马组织中老年斑的数量显著下降,APP蛋白含量并没有发生显著改变,而Aβ42及BACE1的蛋白含量均显著下降,并且Morris水迷宫实验其逃逸时间和逃逸距离均显著减少。但经GNE-317处理后,SEG组和EXG组小鼠分别与SE组和EX组小鼠相比,老年斑数量均显著上升,APP蛋白含量同样无显著改变,而Aβ42及BACE1的蛋白含量均显著上升,并且其逃逸时间和逃逸距离均显著增加。结论:有氧运动通过增强APP/PS1小鼠大脑皮质和海马组织中PI3K/Akt信号通路活性,降低了BACE1的含量,导致Aβ42蛋白含量降低,有效抑制老年斑的形成。
Objective: Using the PI3 K/Akt signaling pathway specific inhibitor GNE-317 to explore if aerobic exercise inhibits the formation of senile plaques in the cerebral cortex and hippocampus of APP/PS1 mice by enhancing the activity of PI3 K/Akt signaling pathway, so as to provide theoretical basis for conforming that aerobic exercise can prevent Alzheimer's disease. Methods: APP/PS1 male mice were randomly divided into four groups: sedentary group(SE), exercise group(EX), sedentary with GNE-317 treatment group(SEG) and exercise with GNE-317 treatment group(EXG). The mice in the EX and EXG group underwent an 8-week treadmill training, meanwhile the mice in the SEG and EXG group were given a treatment with GNE-317 for 8 weeks. Morris water maze experiment was performed in the 9 th week to test the cognitive function of the mice. After morris water maze experiment, cerebral cortex and hippocampus were isolated. The number of senile plaques in each group was observed by immunohistochemistry, and the protein levels of APP, Aβ42 and BACE1 were assayed by Western blot. Results: After 8 weeks of treadmill training, compared with SE, the number of senile plaques of EX was decreased significantly, APP protein was not changed, while the expression levels of Aβ42 and BACE1 were decreased significantly, and in the morris water maze the escape time and distance were reduced significantly. But after GNE-317 treatment, compared with SE and EX,the number of senile plaques of SEG and EXG was increased significantly, and there were no significant differences in APP protein either, while the protein levels of Aβ42 and BACE1 were increased significantly, and in the morris water maze both escape time and distance were significantly increased. Conclusion: Aerobic exercise can reduce the content of BACE1, leading to the reduction of Aβ protein by enhancing the activity of the PI3 K/Akt pathway in the cortex and hippocampus of APP/PS1 mice, so as to inhibit the formation of senile plaques effectively.
Objective: Using the PI3 K/Akt signaling pathway specific inhibitor GNE-317 to explore if aerobic exercise inhibits the formation of senile plaques in the cerebral cortex and hippocampus of APP/PS1 mice by enhancing the activity of PI3 K/Akt signaling pathway, so as to provide theoretical basis for conforming that aerobic exercise can prevent Alzheimer's disease. Methods: APP/PS1 male mice were randomly divided into four groups: sedentary group(SE), exercise group(EX), sedentary with GNE-317 treatment group(SEG) and exercise with GNE-317 treatment group(EXG). The mice in the EX and EXG group underwent an 8-week treadmill training, meanwhile the mice in the SEG and EXG group were given a treatment with GNE-317 for 8 weeks. Morris water maze experiment was performed in the 9 th week to test the cognitive function of the mice. After morris water maze experiment, cerebral cortex and hippocampus were isolated. The number of senile plaques in each group was observed by immunohistochemistry, and the protein levels of APP, Aβ42 and BACE1 were assayed by Western blot. Results: After 8 weeks of treadmill training, compared with SE, the number of senile plaques of EX was decreased significantly, APP protein was not changed, while the expression levels of Aβ42 and BACE1 were decreased significantly, and in the morris water maze the escape time and distance were reduced significantly. But after GNE-317 treatment, compared with SE and EX,the number of senile plaques of SEG and EXG was increased significantly, and there were no significant differences in APP protein either, while the protein levels of Aβ42 and BACE1 were increased significantly, and in the morris water maze both escape time and distance were significantly increased. Conclusion: Aerobic exercise can reduce the content of BACE1, leading to the reduction of Aβ protein by enhancing the activity of the PI3 K/Akt pathway in the cortex and hippocampus of APP/PS1 mice, so as to inhibit the formation of senile plaques effectively.
引文
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张瑞萍,张波,钱帅伟,等,2017.运动干预改善脑学习记忆功能分子机制的研究进展[J].中国体育科技,53(2):119-124,138.
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CAPPAI R,BARNHAM K J,2008.Delineating the mechanism of Alzheimer’s disease A beta peptide neurotoxicity[J].Neurochem Res,33(3):526-532.
DONMEZ G,WANG D,COHEN D E,et al.,2010.SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10[J].Cell,142(2):320-332.
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FANG G L,ZHAO J X,LI P F,et al.,2017.Long-term treadmill exercise inhibits neuronal cell apoptosis and reduces tau phosphorylation in the cerebral cortex and hippocampus of aged rats[J].Sci Bull,62(11):755-757.
HAASS C,SCHLOSSMACHER M G,Hung A Y,et al.,1992.Amyloid beta-peptide is produced by cultured cells during normal metabolism[J].Nat,359(6393):322-325.
HE X L,YAN N,CHEN X S,et al.,2016.Hydrogen sulfide down-regulates BACE1 and PS1 via activating PI3K/Akt pathway in the brain of APP/PS1 transgenic mouse[J].Pharmacolo R,68(5):975-982.
KANG E B,KWON I S,KOO J H,et al.,2013.Treadmill exercise represses neuronal cell death and inflammation during Abeta-induced ER stress by regulating unfolded protein response in aged presenilin2 mutant mice[J].Apoptosis,18(11):1332-1347.
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LOK K,ZHAO H,SHEN H,et al.,2013.Characterization of the APP/PS1 mouse model of Alzheimer’s disease in senescence accelerated background[J].Neurosci Lett,557:84-89.
MIROCHNIC S,WOLF S,STAUFENBIEL M,et al.,2009.Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease[J].Hippocampus,19(10):1008-1018.
SALPHATI L,HEFFRON T P,ALICKE B,et al.,2012.Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier[J].Clin Cancer Res,18(22):6239-6248.
SALPHATI L,SHAHIDI-LATHAM S,QUIASON C,et al.,2014.Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib(GDC-0941)and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging[J].Drug Metab Dispos:Biol Fate Chem,42(7):1110-1116.
WILLNOW T E,ANDERSEN O M,2013.Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease[J].J cell sci,126(13):2751-2760.
YAN Y,WANG C,2006.Abeta42 is more rigid than Abeta40 at the Cterminus:implications for Abeta aggregation and toxicity[J].J Mol Biol,364(5):853-862.2018-12-27 2019-01-10
房国梁,田野,赵杰修,等,2017.有氧运动对肥胖大鼠海马组织tau蛋白磷酸化水平及PI3K/Akt信号通路的影响[J].中国运动医学杂志,36(5):375-382.
付鹏宇,龚丽景,胡扬,2018.运动对棕色脂肪功能的影响及作用机制[J].体育科学,38(11):92-97.
田振军,李明晓,XI Lei,2018.FGF21作为运动因子在有氧运动抑制心梗心肌细胞凋亡中的作用及其机制探讨[J].体育科学,38(12):35-44,67.
徐波,李百侠,赵娜,等,2018.运动通过改善线粒体功能预防和缓解AD的研究进展[J].体育科学,38(9):72-77,97.
赵娜,徐波,张利,等,2018.运动提高脑细胞自噬水平预防与缓解AD的研究进展[J].中国体育科技,54(3):98-104.
张琳,吴迎,曾凡星,等,2017.PI3K/Akt和MAPK信号通路平衡在运动调控高血压血管平滑肌表型转换中的作用[J].中国体育科技,53(6):108-116.
张瑞萍,张波,钱帅伟,等,2017.运动干预改善脑学习记忆功能分子机制的研究进展[J].中国体育科技,53(2):119-124,138.
ADLARD P A,PERREAU V M,POP V,et al.,2005.Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease[J].J Neurosci,25(17):4217-4221.
BLENNOW K,DE LEON M J,ZETTERBERG H,2006.Alzheimer’s disease[J].Lancet,368(9533):387-403.
CAPPAI R,BARNHAM K J,2008.Delineating the mechanism of Alzheimer’s disease A beta peptide neurotoxicity[J].Neurochem Res,33(3):526-532.
DONMEZ G,WANG D,COHEN D E,et al.,2010.SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10[J].Cell,142(2):320-332.
FANG G L,ZHANG D C,ZHANG L,et al.,2018.Long-term aerobic exercise reduces tau phosphorylation by activating the PI3K/AKTpathway in the hippocampus of APP/PS1 mice[J].J Mech Med Biol,18(8):14.
FANG G L,ZHAO J X,LI P F,et al.,2017.Long-term treadmill exercise inhibits neuronal cell apoptosis and reduces tau phosphorylation in the cerebral cortex and hippocampus of aged rats[J].Sci Bull,62(11):755-757.
HAASS C,SCHLOSSMACHER M G,Hung A Y,et al.,1992.Amyloid beta-peptide is produced by cultured cells during normal metabolism[J].Nat,359(6393):322-325.
HE X L,YAN N,CHEN X S,et al.,2016.Hydrogen sulfide down-regulates BACE1 and PS1 via activating PI3K/Akt pathway in the brain of APP/PS1 transgenic mouse[J].Pharmacolo R,68(5):975-982.
KANG E B,KWON I S,KOO J H,et al.,2013.Treadmill exercise represses neuronal cell death and inflammation during Abeta-induced ER stress by regulating unfolded protein response in aged presenilin2 mutant mice[J].Apoptosis,18(11):1332-1347.
LIU H L,ZHAO G,ZHANG H,et al.,2013.Long-term treadmill exercise inhibits the progression of Alzheimer’s disease-like neuropathology in the hippocampus of APP/PS1 transgenic mice[J].BBrain Res,256:261-272.
LOK K,ZHAO H,SHEN H,et al.,2013.Characterization of the APP/PS1 mouse model of Alzheimer’s disease in senescence accelerated background[J].Neurosci Lett,557:84-89.
MIROCHNIC S,WOLF S,STAUFENBIEL M,et al.,2009.Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease[J].Hippocampus,19(10):1008-1018.
SALPHATI L,HEFFRON T P,ALICKE B,et al.,2012.Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier[J].Clin Cancer Res,18(22):6239-6248.
SALPHATI L,SHAHIDI-LATHAM S,QUIASON C,et al.,2014.Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib(GDC-0941)and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging[J].Drug Metab Dispos:Biol Fate Chem,42(7):1110-1116.
WILLNOW T E,ANDERSEN O M,2013.Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease[J].J cell sci,126(13):2751-2760.
YAN Y,WANG C,2006.Abeta42 is more rigid than Abeta40 at the Cterminus:implications for Abeta aggregation and toxicity[J].J Mol Biol,364(5):853-862.2018-12-27 2019-01-10