中老年小鼠通过长期运动改善Aβ1-42诱导的认知功能障碍

doi:10.13418/j.issn.1001-165x.2022.1.08

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中国临床解剖学杂志 ›› 2022, Vol. 40 ›› Issue (1) : 39-44. DOI: 10.13418/j.issn.1001-165x.2022.1.08

实验研究

中老年小鼠通过长期运动改善Aβ1-42诱导的认知功能障碍

张卫国，　杨娜，　杨静，　刘雪芹，　赵云鹤*

作者信息 +

Long-term exercise ameliorates cognitive disorder induced by Aβ1-42 in middle-aged and elderly mice

Zhang Weiguo, Yang Na, Yang Jing, Liu Xueqin, Zhao Yunhe*

Author information +

文章历史 +

摘要

目的　观察中老年小鼠通过长期自主跑轮运动改善β淀粉样蛋白1-42（Aβ1-42）所致认知功能障碍及其机制。方法　中老年BABL/c小鼠（12月龄）随机分为4组，①溶剂对照静坐组（VS），②溶剂对照长期自主跑轮运动组（VR），③Aβ1-42静坐对照组（AS），④Aβ1-42长期自主跑轮运动组（AR），按分组条件分别予以自主跑轮或静坐6个月，双侧海马注射Aβ1-42或等量溶剂。注射两周后进行相关检测。结果　Western blot显示中老年小鼠长期运动致海马泛素化蛋白下降0.2倍（P<0.05）。新物体识别实验显示AR组新物体识别指数高于AS组0.42倍（P<0.05）；Y迷宫自发交替实验显示AR组的入臂正确率较AS组升高0.21倍（P<0.05）。荧光分光光度检测显示AR组海马蛋白酶体活性高于AS组0.18倍（P<0.05）；Western blot显示AR组小鼠海马泛素化蛋白沉积较AS组小鼠减少0.21倍（P<0.05）；免疫组化结果显示AR组Aβ1-42沉积减少（P<0.01）。结论　中老年小鼠长期自主跑轮运动可维持海马蛋白酶体活性，改善Aβ1-42导致的认知功能障碍。

Abstract

Objective　To observe the mechanism of cognitive dysfunction caused by Aβ-amyloid 1-42 (Aβ1-42) in middle-aged and elderly mice by long-term exercise.　Methods 　12-month-old BABL/c mice were randomly divided into the following four groups:①a vehicle control sedentary group (VS),②a vehicle control long-term voluntary running wheel exercise group (VR), ③an Aβ1-42 sedentary group (AS),④an Aβ1-42 long-term voluntary running wheel exercise group (AR). Voluntary running wheel exercise or sedentary for 6 months was performed according to the grouping conditions. The bilateral hippocampus was injected with Aβ1-42 or equivalent solvent for 6 months. Tests were performed two weeks after injection. Results　Western blotting results showed that the accumulation of ubiquitinated protein in the hippocampus of 12-month-old BABL/c mice after long-term voluntary exercise was significantly lower than that in the sedentary group by about 0.2 times (P<0.05). The novel object recognition experiment showed that the preference index in the AR group was 0.42 times higher than that in the AS group（P<0.05). The spontaneous alternation experiment of Y maze showed that the correct rate of arm entry in AR group increased than that in AS group by about 0.21 times (P<0.05). The proteasome activity of AR hippocampus was significantly higher than that of AS group by about 0.18 times (P<0.05). Western blotting results showed the accumulation of ubiquitinated protein in the hippocampus in the AR group was significantly lower than that of AS group by about 0.21 times (P<0.05). Immunohistochemical results showed that Aβ1-42 deposition in AR group was lesser（P<0.01).　Conclusions Middle-aged and elderly mice can maintain hippocampal proteasome activity and improve the cognitive dysfunction caused by Aβ1-42 through long-term voluntary running wheel exercise.

导出引用

张卫国, 　杨娜, 　杨静, 　刘雪芹, 　赵云鹤. 中老年小鼠通过长期运动改善Aβ1-42诱导的认知功能障碍[J]. 中国临床解剖学杂志. 2022, 40(1): 39-44 https://doi.org/10.13418/j.issn.1001-165x.2022.1.08

Zhang Weiguo, Yang Na, Yang Jing, Liu Xueqin, Zhao Yunhe. Long-term exercise ameliorates cognitive disorder induced by Aβ1-42 in middle-aged and elderly mice[J]. Chinese Journal of Clinical Anatomy. 2022, 40(1): 39-44 https://doi.org/10.13418/j.issn.1001-165x.2022.1.08

中图分类号： R322.8

参考文献

[1] Lane CA, Hardy J, Schott JM. Alzheimer's disease[J]. Eur J Neurol, 2018, 25(1): 59-70. DOI: 10.1111/ene.13439.
[2] Xin SH, Tan L, Cao X, et al. Clearance of amyloid beta and tau in Alzheimer's disease: from mechanisms to therapy[J]. Neurotox Res, 2018, 34(3): 733-748. DOI: 10.1007/s12640-018-9895-1.
[3] Thibaudeau TA, Smith DM. A practical review of proteasome pharmacology[J]. Pharmacol Rev, 2019, 71(2): 170-197. DOI: 10.1124/pr.117.015370.
[4] Lopez Salon M, Pasquini L, Besio Moreno M, et al. Relationship between beta-amyloid degradation and the 26S proteasome in neural cells[J]. Exp Neurol, 2003, 180(2): 131-143. DOI: 10.1016/s0014-4886(02)00060-2.
[5] Keck S, Nitsch R, Grune T, et al. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease[J]. J Neurochem, 2003, 85(1): 115-122. DOI: 10.1046/j.1471-4159.2003.01642.x.
[6] Niu XJ, Zhao YH, Yang N, et al. Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis[J]. Stem Cells, 2020, 38(2): 246-260. DOI: 10.1002/stem.3102.
[7] Choi SH, Bylykbashi E, Chatila ZK, et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model[J]. Science, 2018, 361(6406): eaan8821. DOI: 10.1126/science.aan8821.
[8] Lopez Sanchez MIG, van Wijngaarden P, Trounce IA. Amyloid precursor protein-mediated mitochondrial regulation and Alzheimer's disease[J]. Br J Pharmacol, 2019, 176(18): 3464-3474. DOI: 10.1111/bph.14554.
[9] Paxinos G, Franklin KBJ. Paxinos and Franklin's the mouse brain in stereotaxic coordinates[M]. Amsterdam: Academic Press, Elsevier, 2019: 69.
[10] 黄菲菲, 王必慧, 赵泳媚, 等. 运动上调蛋白酶体活性促进SVZ区神经发生[J]. 中国运动医学杂志, 2019, 38(2): 126-130. DOI: 10.3969/j.issn.1000-6710.2019.02.007.
[11]Opattova A, Cente M, Novak M, et al. The ubiquitin proteasome system as a potential therapeutic target for treatment of neurodegenerative diseases[J]. Gen Physiol Biophys, 2015, 34(4): 337-352. DOI: 10.4149/gpb_2015024.
[12]余锋, 贾芳芳. 运动调控GSK-3β介导阿尔茨海默症的机制探析[J]. 南京体育学院学报,2020, 19(2): 52-59. DOI: 10.15877/j.cnki.nsin. 2020. 02.008.
[13] Leng FD, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here[J]? Nat Rev Neurol, 2021, 17(3): 157-172. DOI: 10.1038/s41582-020-00435-y.
[14]Atri A. The Alzheimer's disease clinical spectrum: diagnosis and management[J]. Med Clin North Am, 2019,103(2): 263-293. DOI: 10.1016/j.mcna.2018.10.009.
[15]Hassan WM, Merin DA, Fonte V, et al. AIP-1 ameliorates beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model[J]. Hum Mol Genet, 2009, 18(15): 2739-2747. DOI: 10.1093/hmg/ddp209.
[16]Himeno E, Ohyagi Y, Ma L, et al. Apomorphine treatment in Alzheimer mice promoting amyloid-beta degradation[J]. Ann Neurol, 2011, 69(2): 248-256. DOI: 10.1002/ana.22319.
[17]Nakamura N, Ohyagi Y, Imamura T, et al. Apomorphine therapy for neuronal insulin resistance in a mouse model of Alzheimer's disease[J]. J Alzheimers Dis, 2017, 58(4): 1151-1161. DOI: 10.3233/JAD-160344.
[18]Medina DX, Caccamo A, Oddo S. Methylene blue reduces abeta levels and rescues early cognitive deficit by increasing proteasome activity[J]. Brain Pathol, 2011, 21(2): 140-149. DOI: 10.1111/j.1750-3639.2010.00430.x.
[19]Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides[J]. J Biol Chem, 2005, 280(45): 37377-37382. DOI: 10.1074/jbc.M508246200.