跑步锻炼延缓APP/PS1双转基因小鼠内侧前额叶皮质树突棘数量的丢失
|
摘要
目的运用无偏体视学方法精确定量研究跑步锻炼对中老年APP/PS1双转基因模型小鼠内侧前额叶皮质树突棘的作用。方法 12月龄的雄性APP/PS1转基因小鼠分为对照组和跑步组,并将同窝生野生型小鼠作为野生组,每组10只,共30只。对跑步组小鼠进行4个月的跑步锻炼;运用Morris水迷宫方法测试3组小鼠的空间学习记忆能力;运用无偏体视学方法精确定量3组小鼠内侧前额叶皮质树突棘的数量。结果在隐藏平台实验中,对照组平均逃避潜伏期明显大于跑步组和野生组(F=15.738,P<0.001),在空间探索实验中,3组小鼠穿台次数、目标象限游泳时间、目标象限游泳距离百分比差异都有统计学意义(P<0.001);对照组内侧前额叶皮质的树突棘总数显著小于跑步组和野生组(P=0.029,P=0.005)。结论跑步锻炼可以延缓APP/PS1双转基因AD模型小鼠内侧前额叶皮质树突棘的丢失。
Objective To investigate the effect of running exercise on the number of dendritic spines in the medial prefrontal cortex in an APP/PS1 double transgenic mouse model of Alzheimer's disease(AD). Methods Twelve-month-old male APP/PS1 transgenic mice were randomly divided into control group and running exercise group(n=10), and 10 wild-type littermates of the transgenic mice served as the wild-type control group. The mice in the running exercise group were subjected to forced running exercise for 4 months. The spatial learning and memory abilities of the mice were tested using Morris water maze test, and the total number of the dendritic spines in the medial prefrontal cortex was accurately determined using a unbiased stereological method. Results In the hidden platform task, the escape latency was significantly longer in the control group than in the wild-type control group and the running exercise group(F=15.738, P<0.001). In the probe task, the frequency of platform location crosses, the time spending in the target quadrant and the percentage distance in the target quadrant all differed significantly among the 3 groups(P<0.001). The total number of dendritic spines in the medial prefrontal cortex was significantly smaller in the control group than in the running exercise group(P=0.029) and the wild-type control group(P=0.005). Conclusion Running exercise can reduce dendritic spine loss in the medial prefrontal cortex of APP/PS1 transgenic mouse models of AD.
Objective To investigate the effect of running exercise on the number of dendritic spines in the medial prefrontal cortex in an APP/PS1 double transgenic mouse model of Alzheimer's disease(AD). Methods Twelve-month-old male APP/PS1 transgenic mice were randomly divided into control group and running exercise group(n=10), and 10 wild-type littermates of the transgenic mice served as the wild-type control group. The mice in the running exercise group were subjected to forced running exercise for 4 months. The spatial learning and memory abilities of the mice were tested using Morris water maze test, and the total number of the dendritic spines in the medial prefrontal cortex was accurately determined using a unbiased stereological method. Results In the hidden platform task, the escape latency was significantly longer in the control group than in the wild-type control group and the running exercise group(F=15.738, P<0.001). In the probe task, the frequency of platform location crosses, the time spending in the target quadrant and the percentage distance in the target quadrant all differed significantly among the 3 groups(P<0.001). The total number of dendritic spines in the medial prefrontal cortex was significantly smaller in the control group than in the running exercise group(P=0.029) and the wild-type control group(P=0.005). Conclusion Running exercise can reduce dendritic spine loss in the medial prefrontal cortex of APP/PS1 transgenic mouse models of AD.
引文
[1] KEOGH-BROWN M R,JENSEN H T,ARRIGHI H M,et al.The impact of Alzheimer’s disease on the Chinese economy[J].EBio Medicine,2016,4:184-190.DOI:10.1016/j.ebiom.2015.12.019.
[2] XIA X,JIANG Q L,MCDERMOTT J,et al.Aging and Alzheimer’s disease:Comparison and associations from molecular to system level[J].Aging Cell,2018,17(5):e12802.DOI:10.1111/ acel.12802.
[3] TOMPARY A,DAVACHI L.Consolidation promotes the emergence of representational overlap in the hippocampus and medial prefrontal cortex[J].Neuron,2017,96(1):228-241.e5.DOI:10.1016/j.neuron.2017.09.005.
[4] LI C M,ZHENG J,WANG J,et al.An fMRI stroop task study of prefrontal cortical function in normal aging,mild cognitive impairment,and Alzheimer’s disease[J].Curr Alzheimer Res,2009,6(6):525-530.
[5] LO A C,ISCRU E,BLUM D,et al.Amyloid and tau neuropathology differentially affect prefrontal synaptic plasticity and cognitive performance in mouse models of Alzheimer’s disease[J].J Alzheimers Dis,2013,37(1):109-125.DOI:10.3233/JAD-122296.
[6] ZOU C Y,MONTAGNA E,SHI Y,et al.Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease[J].Acta Neuropathol,2015,129(6):909-920.DOI:10.1007/s00401-015-1421-4.
[7] JACOBSEN J S,WU C C,REDWINE J M,et al.Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease[J].Proc Natl Acad Sci U S A,2006,103(13):5161- 5166.DOI:10.1073/pnas.0600948103.
[8] BROWN B M,PEIFFER J J,MARTINS R N.Multiple effects of physical activity on molecular and cognitive signs of brain aging:can exercise slow neurodegeneration and delay Alzheimer’s disease?[J].Mol Psychiatry,2013,18(8):864-874.DOI:10.1038/mp.2012.162.
[9] 唐炜,晁凤蕾,蒋林,等.跑步锻炼减少中老年APP/PS1双转基因AD小鼠海马齿状回内树突棘丢失[J].重庆医科大学学报,2017,42(6):707-712.DOI:10.13406/j.cnki.cyxb.001184.TANG W,CHAO F L,JIANG L,et al.Running exercise reduces dendritic spine loss in the dentate gyrus of the hippocampus in middle-aged APP/PS1 transgenic AD mice[J].J Chongqing Med Univ,2017,42(6):707-712.DOI:10.13406/j.cnki.cyxb.001184.
[10] CROXSON P L,KYRIAZIS D A,BAXTER M G.Cholinergic modulation of a specific memory function of prefrontal cortex[J].Nat Neurosci,2011,14(12):1510-1512.DOI:10.1038/nn.2971.
[11] KO J.Neuroanatomical substrates of rodent social behavior:the medial prefrontal cortex and its projection patterns[J].Front Neural Circuits,2017,11:41.DOI:10.3389/fncir.2017.00041.
[12] BROD G,WERKLE-BERGNER M,SHING Y L.The influence of prior knowledge on memory:A developmental cognitive neuroscience perspective[J].Front Behav Neurosci,2013,7:139.DOI:10.3389/fnbeh.2013.00139.
[13] VAN DE WERD H J,UYLINGS H B.Comparison of (stereotactic) parcellations in mouse prefrontal cortex[J].Brain Struct Funct,2014,219(2):433-459.DOI:10.1007/s00429-013-0630-7.
[14] HUEY E D,LEE S,CHERAN G,et al.Brain regions involved in arousal and reward processing are associated with apathy in Alzheimer’s disease and frontotemporal dementia[J].J Alzheimers Dis,2017,55(2):551-558.DOI:10.3233/JAD-160107.
[15] HORNBERGER M,YEW B,GILARDONI S,et al.Ventromedial-frontopolar prefrontal cortex atrophy correlates with insight loss in frontotemporal dementia and Alzheimer’s disease[J].Hum Brain Mapp,2014,35(2):616-626.DOI:10.1002/hbm.22200.
[16] FRANKLAND P W,BONTEMPI B.Fast track to the medial prefrontal cortex[J].Proc Natl Acad Sci U S A,2006,103(3):509-510.DOI:10.1073/pnas.0510133103.
[17] GROOT C,HOOGHIEMSTRA A M,RAIJMAKERS P G,et al.The effect of physical activity on cognitive function in patients with dementia:A meta-analysis of randomized control trials[J].Ageing Res Rev,2016,25:13-23.DOI:10.1016/j.arr.2015.11.005.
[18] BLOOM G S.Amyloid-β and tau:the trigger and bullet in Alzheimer disease pathogenesis[J].JAMA Neurol,2014,71(4):505-508.DOI:10.1001/jamaneurol.2013.5847.
[19] XU Z Q,ZHANG L Q,WANG Q,et al.Aerobic exercise combined with antioxidative treatment does not counteract moderate- or mid-stage Alzheimer-like pathophysiology of APP/PS1 mice[J].CNS Neurosci Ther,2013,19(10):795-803.DOI:10.1111/cns.12139.
[20] CHO J,SHIN M K,KIM D,et al.Treadmill running reverses cognitive declines due to alzheimer disease[J].Med Sci Sports Exerc,2015,47(9):1814-1824.DOI:10.1249/MSS.0000000000000612.
[21] ZHAO G,LIU H L,ZHANG H,et al.Treadmill exercise enhances synaptic plasticity,but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice[J].Neuroscience,2015,298:357-366.DOI:10.1016/j.neuroscience.2015.04.038.
[22] LAMBERT M P,BARLOW A K,CHROMY B A,et al.Diffusible,nonfibrillar ligands derived from A 1-42 are potent central nervous system neurotoxins[J].Proc Natl Acad Sci U S A,1998,95(11):6448-6453.DOI:10.1073/pnas.95.11.6448.
[23] HAO J D,JANSSEN W G,TANG Y,et al.Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys[J].J Comp Neurol,2003,465(4):540-550.DOI:10.1002/cne.10837.
[24] ZHOU C N,CHAO F L,ZHANG Y,et al.Fluoxetine delays the cognitive function decline and synaptic changes in a transgenic mouse model of early Alzheimer’s disease[J].J Comp Neurol,2019,527(8):1378-1387.DOI:10.1002/cne.24616.
[2] XIA X,JIANG Q L,MCDERMOTT J,et al.Aging and Alzheimer’s disease:Comparison and associations from molecular to system level[J].Aging Cell,2018,17(5):e12802.DOI:10.1111/ acel.12802.
[3] TOMPARY A,DAVACHI L.Consolidation promotes the emergence of representational overlap in the hippocampus and medial prefrontal cortex[J].Neuron,2017,96(1):228-241.e5.DOI:10.1016/j.neuron.2017.09.005.
[4] LI C M,ZHENG J,WANG J,et al.An fMRI stroop task study of prefrontal cortical function in normal aging,mild cognitive impairment,and Alzheimer’s disease[J].Curr Alzheimer Res,2009,6(6):525-530.
[5] LO A C,ISCRU E,BLUM D,et al.Amyloid and tau neuropathology differentially affect prefrontal synaptic plasticity and cognitive performance in mouse models of Alzheimer’s disease[J].J Alzheimers Dis,2013,37(1):109-125.DOI:10.3233/JAD-122296.
[6] ZOU C Y,MONTAGNA E,SHI Y,et al.Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease[J].Acta Neuropathol,2015,129(6):909-920.DOI:10.1007/s00401-015-1421-4.
[7] JACOBSEN J S,WU C C,REDWINE J M,et al.Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease[J].Proc Natl Acad Sci U S A,2006,103(13):5161- 5166.DOI:10.1073/pnas.0600948103.
[8] BROWN B M,PEIFFER J J,MARTINS R N.Multiple effects of physical activity on molecular and cognitive signs of brain aging:can exercise slow neurodegeneration and delay Alzheimer’s disease?[J].Mol Psychiatry,2013,18(8):864-874.DOI:10.1038/mp.2012.162.
[9] 唐炜,晁凤蕾,蒋林,等.跑步锻炼减少中老年APP/PS1双转基因AD小鼠海马齿状回内树突棘丢失[J].重庆医科大学学报,2017,42(6):707-712.DOI:10.13406/j.cnki.cyxb.001184.TANG W,CHAO F L,JIANG L,et al.Running exercise reduces dendritic spine loss in the dentate gyrus of the hippocampus in middle-aged APP/PS1 transgenic AD mice[J].J Chongqing Med Univ,2017,42(6):707-712.DOI:10.13406/j.cnki.cyxb.001184.
[10] CROXSON P L,KYRIAZIS D A,BAXTER M G.Cholinergic modulation of a specific memory function of prefrontal cortex[J].Nat Neurosci,2011,14(12):1510-1512.DOI:10.1038/nn.2971.
[11] KO J.Neuroanatomical substrates of rodent social behavior:the medial prefrontal cortex and its projection patterns[J].Front Neural Circuits,2017,11:41.DOI:10.3389/fncir.2017.00041.
[12] BROD G,WERKLE-BERGNER M,SHING Y L.The influence of prior knowledge on memory:A developmental cognitive neuroscience perspective[J].Front Behav Neurosci,2013,7:139.DOI:10.3389/fnbeh.2013.00139.
[13] VAN DE WERD H J,UYLINGS H B.Comparison of (stereotactic) parcellations in mouse prefrontal cortex[J].Brain Struct Funct,2014,219(2):433-459.DOI:10.1007/s00429-013-0630-7.
[14] HUEY E D,LEE S,CHERAN G,et al.Brain regions involved in arousal and reward processing are associated with apathy in Alzheimer’s disease and frontotemporal dementia[J].J Alzheimers Dis,2017,55(2):551-558.DOI:10.3233/JAD-160107.
[15] HORNBERGER M,YEW B,GILARDONI S,et al.Ventromedial-frontopolar prefrontal cortex atrophy correlates with insight loss in frontotemporal dementia and Alzheimer’s disease[J].Hum Brain Mapp,2014,35(2):616-626.DOI:10.1002/hbm.22200.
[16] FRANKLAND P W,BONTEMPI B.Fast track to the medial prefrontal cortex[J].Proc Natl Acad Sci U S A,2006,103(3):509-510.DOI:10.1073/pnas.0510133103.
[17] GROOT C,HOOGHIEMSTRA A M,RAIJMAKERS P G,et al.The effect of physical activity on cognitive function in patients with dementia:A meta-analysis of randomized control trials[J].Ageing Res Rev,2016,25:13-23.DOI:10.1016/j.arr.2015.11.005.
[18] BLOOM G S.Amyloid-β and tau:the trigger and bullet in Alzheimer disease pathogenesis[J].JAMA Neurol,2014,71(4):505-508.DOI:10.1001/jamaneurol.2013.5847.
[19] XU Z Q,ZHANG L Q,WANG Q,et al.Aerobic exercise combined with antioxidative treatment does not counteract moderate- or mid-stage Alzheimer-like pathophysiology of APP/PS1 mice[J].CNS Neurosci Ther,2013,19(10):795-803.DOI:10.1111/cns.12139.
[20] CHO J,SHIN M K,KIM D,et al.Treadmill running reverses cognitive declines due to alzheimer disease[J].Med Sci Sports Exerc,2015,47(9):1814-1824.DOI:10.1249/MSS.0000000000000612.
[21] ZHAO G,LIU H L,ZHANG H,et al.Treadmill exercise enhances synaptic plasticity,but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice[J].Neuroscience,2015,298:357-366.DOI:10.1016/j.neuroscience.2015.04.038.
[22] LAMBERT M P,BARLOW A K,CHROMY B A,et al.Diffusible,nonfibrillar ligands derived from A 1-42 are potent central nervous system neurotoxins[J].Proc Natl Acad Sci U S A,1998,95(11):6448-6453.DOI:10.1073/pnas.95.11.6448.
[23] HAO J D,JANSSEN W G,TANG Y,et al.Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys[J].J Comp Neurol,2003,465(4):540-550.DOI:10.1002/cne.10837.
[24] ZHOU C N,CHAO F L,ZHANG Y,et al.Fluoxetine delays the cognitive function decline and synaptic changes in a transgenic mouse model of early Alzheimer’s disease[J].J Comp Neurol,2019,527(8):1378-1387.DOI:10.1002/cne.24616.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |