身体活动对阿尔兹海默病的预防及改善作用机制的研究进展
2022-06-08
关键词:阿尔兹海默病;身体活动;炎症反应;自噬;血脑屏障
阿尔兹海默病(Alzheimer’s disease,AD)是一种神经退行性疾病,表现为记忆功能及认知功能的进行性退化,主要的病理特点是 β 淀粉样蛋白沉积及 tau 蛋白过度磷酸化[1]。随着社会老龄化进展及人口寿命的延长,AD 已快速成为全球性问题。尽管针对 AD 的发病机制、诊断治疗已成为全世界的研究热点,但目前仍然缺乏有效的治疗方法。因此,AD 的预防就显得更为重要。越来越多的证据表明,身体活动可能为一种实用、经济,并且可行的预防和改善 AD 的方法。多项研究显示,日常身体活动能降低 AD 的发生风险[2-4]。2019 年哥本哈根共识声明(体力活动与衰老)中也指出,成年期身体活动能减慢或延迟年龄相关的认知功能下降及神经退行性疾病的发生[5]。英国、美国、欧洲一项人群分析显示,在 AD 发病风险因素中,所占比例最大的就是缺乏身体活动[6]。对 AD 患者来说,身体活动也能帮助其改善认知、记忆功能[7-9]。近年来,关于身体活动对AD 的预防及改善作用机制研究也越来越多,越来越深入,本文中就其进行概述,为更加有效地开展早期预防及综合治疗 AD 提供思路及依据。
(TNF-α)、IL-6 等[11]。Xiong 等[12]使用 APP/PS1 转基因AD 小鼠模型进行研究发现,长期跑台运动能显着减少活化的小胶质细胞,从而显着改善 AD 小鼠的空间学习及记忆功能,但是,对海马区及大脑皮质 Aβ 斑块的沉积没有影响,因此,推测身体活动对空间学习和记忆功能的影响不是 Aβ 斑块减少的结果。低水平的全身炎症反应通常发生于代谢综合征、胰岛素抵抗、高血压、血脂异常及肥胖等疾病[13]。研究发现,超重、肥胖的糖尿病患者血液中炎症因子水平升高,如 IL-1β、IL-6 和 TNF-α 等,而糖尿病与 AD 在病理发生方面有诸多类似的地方,这些炎症因子在 AD 患者大脑、脑脊液及血液中也升高[14-16]。而且,低水平的全身炎症反应会明显影响血脑屏障,使其通透性增加,炎症因子更易穿过,促进大脑胰岛素抵抗,并导致线粒体功能异常及Aβ 沉积[17]。伴随着胰岛素抵抗、脂代谢异常,神经酰胺的产生增加,这类分子也可以穿过血脑屏障,导致炎症反应并干扰大脑胰岛素信号通路[18]。研究发现,身体活动能改善脂代谢异常,从而降低神经酰胺水平,减轻炎症反应[19-20]。此外,骨骼肌作为机体最大的器官,也能产生并释放炎症因子,如 IL-6、IL-8、IL-15 和 TNF-α,它们被称为肌肉因子(myokine)[21]。Handschin 等[22]发现,身体活动能通过上调过氧化物酶体增殖物激活受体-γ 辅助活化因子-1α(PGC -1α)广泛抑制肌肉因子的表达。
血流量减少更加明显[34-36]。身体活动可以通过改善脑血管功能阻止或延缓 AD 的发生。研究发现,身体活动能增加脑血流量,缓解年龄对大脑血流量的影响,改善认知功能[37]。然而,最近的一项研究发现,对轻中度 AD 患者进行中高强度的有氧运动干预 16 周后,大脑整体及局部血流量并无改善,可能由于 AD 症状出现前若干年,就已经存在脑血流灌注量的逐渐减少,而从 AD 症状出现到进展为轻中度,观察到的脑血流量变化已经微乎其微,即脑血流量已相对固定,不易被改变,因此身体活动对其影响不明显,也可能与干预时间较短有关系[38]。因此,关于身体活动对 AD 患者大脑血流量的影响,还要综合考虑年龄、运动强度及干预时间等因素,进行进一步研究。
维持突触正常功能也是非常重要的。同时,身体活动使很多调节突触效能的基因表达增加,如调节突触小泡形成、释放、再摄取的突触前成分,突触后的 γ-氨基丁酸及谷氨酸神经递质受体等。而且,身体活动使得维持髓鞘完整性及轴突功能的相关基因表达增加,并能抵消AD 相关的异常转录,但是未发现身体活动对炎症相关基因的表达有强有力的影响。身体活动也能促进神经营养因子,如 BDNF、胰岛素样生长因子(IGF)和血管内皮生长因子(VEGF)等的表达增加[56-58]。研究发现, 身体活动产生的乳酸也能促进 BDNF 的表达[59]。BDNF 在大脑中高表达,在神经细胞增殖、神经元分化、维持神经元生存及正常生理功能、突触可塑性等方面发挥重要作用。多项研究发现,无论动物模型、健康人群还是轻度认知功能障碍者,身体活动都可以使 BDNF 表达增加,而且它能通过血脑屏障进入大脑[12,55-56,60]。即使无意识状态下的肌肉收缩也能使海马区 BDNF 表达增加[61]。BDNF 可以与原肌球蛋白激酶 B 受体结合,启动磷酸化级联反应, 激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路,该信号通路在调节神经细胞突触可塑性、自噬等方面发挥重要作用[62]。然而,身体活动对 mTOR 信号通路的影响目前研究结果尚未一致。研究发现,身体活动后,大脑许多区域如海马区、前额叶皮质、纹状体、下丘脑等部位 mTOR 磷酸化水平增加,有的研究发现,身体活动后,皮质区 mTOR 表达增加,但海马区无变化,也有研究发现身体活动后 24 h,mTOR 有短暂的表达增加,之后并未增加[63-65]。此外,BDNF 促进 α 分泌酶重新分布,裂解 β 淀粉样前体蛋白成为分泌型 α 分泌酶裂解的淀粉样前体蛋白细胞外片段(sAPPα),从而减少 β 淀粉样蛋白的产生[66]。研究发现,sAPPα 具有神经保护及神经营养功能,并可促进神经发生及突触可塑性[67]。
身体活动对 AD 的预防及改善作用机制研究日益深入,尽管有些研究结果不尽相同,但身体活动对 AD 的效果却受到越来越多研究者的认可,无论是预防还是改善 AD,身体活动在其中的作用都将会更加受到重视。未来,随着作用机制研究的不断深入,以及不同人群、不同运动方式、运动时间及运动强度方面长期大样本人群研究的开展,我们将进一步明确身体活动对 AD 的意义。
参考文献
[1] Murman DL. The impact of age on cognition[J]. Semin Hear,2015, 36(3):111-121.
[2] Beckett MW,Ardern CI,Rotondi MA. A meta-analysis of prospective studies on the role of physical activity and the prevention of Alzheimer ’s disease in older adults[J]. BMC Geriatr,2015,15:9. DOI:10.1186/s12877-015-0007-2.
[3] Beydoun MA,Beydoun HA,Gamaldo AA,et al. Epidemiologic stud- ies of modifiable factors associated with cognition and dementia:sys-tematic review and meta-analysis[J]. BMC Public Health,2014,14(643):1-33.
[4] Hamer M,Chida Y. Physical activity and risk of neurodegenerative disease:a systematic review of prospective evidence[J]. Psychol Med, 2009,39(1):3-11.
[5] Bangsbo J,Blackwell J,Boraxbekk CJ,et al. Copenhagen consensus statement 2019:physical activity and ageing[J]. Br J Sports Med, 2019,53(14):856-858.
[6] Norton S,Matthews FE,Barnes DE,et al. Potential for primary prevention of Alzheimer’s disease:an analysis of population -based data[J]. Lancet Neurol,2014,13(8):788-794.
[7] Ginis KA,Heisz J,Spence JC,et al. Formulation of evidence -based messages to promote the use of physical activity to prevent and man- age Alzheimer's disease[J]. BMC Public Health,2017,17(1):209. DOI:10.1186/s12889-017-4090-5.
[8] Stubbs B,Chen LJ,Chang CY,et al. Accelerometer -assessed light physical activity is protective of future cognitive ability:a longitudinal study among community dwelling older adults[J]. Exp Gerontol, 2017,91:104-109. DOI:10.1016/j.exger.2017.03.003.
[9] Suwabe K,Byun K,Hyodo K,et al. Rapid stimulation of human den- tate gyrus function with acute mild exercise[J]. Proc Natl Acad Sci U S A,2018,115(41):10487-10492.
[10] Calsolaro V,Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions[J]. Alzheimers Dement, 2016,12(6):719-732.
[11] Tejera D,Heneka MT. Microglia in Alzheimer's disease:the good,the bad and the ugly[J]. Curr Alzheimer Res,2016,13(4):370-380.
[12] Xiong JY,Li SC,Sun YX,et al. Long -term treadmill exercise im- proves spatial memory of male APPswe/PS1dE9 mice by regulation of BDNF expression and microglia activation[J]. Biol Sport,2015,32(4):295-300.
[13] León-Pedroza JI,González -Tapia LA,del Olmo-Gil E,et al. Low- grade systemic inflammation and the development of metabolic dis - eases:from the molecular evidence to the clinical practice[J]. Cir Cir, 2015,83(6):543-551.
[14] Reinehr T,Karges B,Meissner T,et al. Inflammatory markers in obese adolescents with type 2 diabetes and their relationship to hepa- tokines and adipokines[J]. J Pediatr,2016,173:131 -135. DOI: 10.1016/j.jpeds.2016.02.055.
[15] Rajkovic N,Zamaklar M,Lalic K,et al. Relationship between obesi- ty,adipocytokines and inflammatory markers in type 2 diabetes:rele- vance for cardiovascular risk prevention[J]. Int J Environ Res Public Health,2014,11(4):4049-4065.
[16] Gironès X,Guimerà A,Cruz -Sánchez CZ,et al. N epsilon -car- boxymethyllysine in brain aging,diabetes mellitus,and Alzheimer's disease[J]. Free Radic Biol Med,2004,36(10):1241-1247.
[17] Grimm A,Friedland K,Eckert A. Mitochondrial dysfunction:the missing link between aging and sporadic Alzheimer's disease[J]. Biogerontology,2016,17(2):281-296.
[18] De la Monte SM. Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides,ER stress,and insulin resistance re- viewed[J]. J Alzheimers Dis,2012,30(Suppl 2):S231-249.
[19] Dubé JJ,Amati F,Toledo FG,et al. Effects of weight loss and exercise on insulin resistance,and intramyocellular triacylglycerol,diacylglyc- erol and ceramide[J]. Diabetologia,2011,54(5):1147-1156.
[20] Kasumov T,Solomon TP,Hwang C. Improved insulin sensitivity after exercise training is linked to reduced plasma C14:0 ceramide in obe- sity and type 2 diabetes[J]. Obesity(Silver Spring),2015,23(7): 1414-1421.
[21] Pedersen BK. Muscles and their myokines[J]. J Exp Biol,2011,214(Pt 2):337-346.
[22] Handschin C,Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease[J]. Nature,2008,454(7203):463- 469.
[23] Toman J,Fiskum G. Influence of aging on membrane permeability transition in brain mitochondria[J]. J Bioenerg Biomembr,2011,43(1):3-10.
[24] Spuch C,Ortolano S,Navarro C. New insights in the amyloid -Beta interaction with mitochondria[J]. J Aging Res,2012,2012:324968. DOI:10.1155/2012/324968.
[25] Marques -Aleixo I,Santos -Alves E,Bal觭a MM,et al. Physical exer- cise improves brain cortex and cerebellum mitochondrial bioenerget- ics and alters apoptotic,dynamic and auto (mito)phagy markers[J]. Neuroscience,2015,301:480 -495. DOI:10.1016/j.neuroscience.2015. 06.027.
[26] Wang X,Su B,Lee HG,et al. Impaired balance of mitochondrial fis- sion and fusion in Alzheimer's disease[J]. J Neurosci,2009,29(28): 9090-9103.
[27] Yan QW,Zhao N,Xia J,et al. Effects of treadmill exercise on mito- chondrial fusion and fission in the hippocampus of APP/PS1 mice[J]. Neurosci Lett,2019,701:84-91. DOI:10.1016/j.neulet.2019.02.030.
[28] Jiang T,Yu JT,Zhu XC. Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease[J]. Pharmacol Res,2014,81:54-63. DOI:10.1016/j.phrs.2014.02.008.
[29] McKnight NC,Zhenyu Y. Beclin 1,an essential component and mas- ter regulator of PI3K-III in health and disease[J]. Curr Pathobiol Rep,2013,1(4):231-238.
[30] Johansen T,Lamark T. Selective autophagy mediated by autophagic adapter proteins[J]. Autophagy,2011,7(3):279-296.
[31] He C,Sumpter R Jr,Levine B. Exercise induces autophagy in periph- eral tissues and in the brain[J]. Autophagy,2012,8(10):1548-1551.
[32] Zhao N,Zhang X,Song C. The effects of treadmill exercise on au - tophagy in hippocampus of APP/PS1 transgenic mice[J]. Neurore- port,2018,29(10):819-825.
[33] Barnes JN,Corkery AT. Exercise improves vascular function,but does this translate to the brain?[J]. Brain Plast,2018,4(1):65-79.
[34] Asllani I,Habeck C,Scarmeas N,et al. Multivariate and univariate analysis of continuous arterial spin labeling perfusion MRI in Alzheimer's disease[J]. J Cereb Blood Flow Metab,2008,28(4): 725-736.
[35] Binnewijzend MA,Kuijer JP,Benedictus MR,et al. Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment:a mark- er for disease severity[J]. Radiology,2013,267(1):221-230.
[36] Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration,cogni- tive impairment,and Alzheimer's disease[J]. J Neurosci Res,2017, 95(4):943-972.
[37] Lucas SJ,Ainslie PN,Murrell CJ,et al. Effect of age on exercise-in- duced alterations in cognitive executive function:relationship to cere- bral perfusion[J]. Exp Gerontol,2012,47(8):541-551.
[38] Van der Kleij LA,Petersen ET,Siebner HR. The effect of physical exercise on cerebral blood flow in Alzheimer's disease[J]. Neuroim- age Clin,2018,20:650-654. DOI:10.1016/j.nicl.2018.09.003.
[39] Bostr觟m P,Wu J,Jedrychowski MP,et al. A PGC1 -α -dependent myokine that drives brown-fat-like development of white fat and ther- mogenesis[J]. Nature,2012,481(7382):463-468.
[40] Lourenco MV,Frozza RL,de Freitas GB. Exercise -linked FNDC5/ irisin rescues synaptic plasticity and memory defects in Alzheimer's models[J]. Nat Med,2019,25(1):165-175.
[41] Wrann CD,White JP,Salogiannnis J,et al. Exercise induces hip-
pocampal BDNF through a PGC-1α/FNDC5 pathway[J]. Cell Metab, 2013,18(5):649-659.
[42] Zhang J,Zhang W. Can irisin be a linker between physical activity and brain function?[J]. Biomol Concepts,2016,7(4):253-258.
[43] Benito E,Barco A. CREB's control of intrinsic and synaptic plastici - ty :implications for CREB - dependent memory models[J]. Trends Neurosci,2010,33(5):230-240.
[44] Chen X,Gan L. An exercise -induced messenger boosts memory in Alzheimer's disease[J]. Nat Med,2019,25(1):20-21.
[45] Li DJ,Li YH,Yuan HB,et al. The novel exercise-induced hormone
irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia[J]. Metabolism,2017,68:31- 42. DOI:10.1016/j.metabol.2016.12.003.
[46] Gamba P,Testa G,Gargiulo S,et al. Oxidized cholesterol as the driv-ing force behind the development of Alzheimer's disease[J]. Front Aging Neurosci,2015,7:119. DOI:10.3389/fnagi.2015.00119.
[47] Zhao Z,Nelson AR,Betsholtz C,et al. Establishment and dysfunction of the blood-brain barrie[r J]. Cell,2015,163(5):1064-1078.
[48] Ma覥kiewicz MA,Szarmach A,Sabisz A,et al. Blood -brain barrier permeability and physical exercise[J]. J Neuroinflammation,2019, 16(1):15. DOI:10.1186/s12974-019-1403-x.
[49] Wolburg H,Lippoldt A. Tight junctions of the blood -brain barrier: development,composition and regulation[J]. Vascul Pharmacol,2002, 38(6):323-337.
[50] Souza PS,Gon觭alves ED,Pedroso GS,et al. Physical exercise attenu- ates experimental autoimmune encephalomyelitis by inhibiting pe- ripheral immune response and blood-brain barrier disruption[J]. Mol Neurobiol,2017,54(6):4723-4737.
[51] de Senna PN,Xavier LL,Bagatini PB,et al. Physical training im- proves non-spatial memory,locomotor skills and the blood brain bar- rier in diabetic rats[J]. Brain Res,2015,1618:75-82. DOI:10.1016/ j.brainres.2015.05.026.
[52] He XF,Liu DX,Zhang Q. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice[J]. Front Mol Neurosci,2017,10:144. DOI: 10.3389/fnmol.2017.00144.
[53] Schlittler M,Goiny M,Agudelo LZ,et al. Endurance exercise increas- es skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans[J]. Am J Physiol Cell Physiol,2016,310(10):C836-840.
[54] Konradsson -Geuken A,Wu HQ,Gash CR,et al. Cortical kynurenic acid bi -directionally modulates prefrontal glutamate levels as as- sessed by microdialysis and rapid electrochemistry[J]. Neuroscience, 2010,169(4):1848-1859.
[55] Berchtold NC,Prieto GA,Phelan M,et al. Hippocampal gene expres- sion patterns linked to late-life physical activity oppose age and AD- related transcriptional decline[J]. Neurobiol Aging,2019,78:142- 154. DOI:10.1016/j.neurobiolaging.2019.02.012.
[56] Tsai CL,Pai MC,Ukropec J,et al. Distinctive effects of aerobic and resistance exercise modes on neurocognitive and biochemical changes in individuals with mild cognitive impairment[J]. Curr Alzheimer Res,2019,16(4):316-332.
[57] Rosa JM,Pazini FL,Olescowicz G,et al. Prophylactic effect of physi- cal exercise on Aβ1 -40 -induced depressive -like behavior:role of BDNF,mTOR signaling,cell proliferation and survival in the hip - pocampus[J]. Prog Neuropsychopharmacol Biol Psychiatry ,2019, 94:109646. DOI:10.1016/j.pnpbp.2019.109646.
[58] E L,Burns JM,Swerdlow RH. Effect of high -intensity exercise on aged mouse brain mitochondria,neurogenesis,and inflammation[J]. Neurobiol Aging,2014,35(11):2574-2583.
[59] Schiffer T,Schulte S,Sperlich B,et al. Lactate infusion at rest in - creases BDNF blood concentration in humans[J].Neurosci Lett, 2011,488(3):234-237.
[60] Saraulli D,Costanzi M,Mastrorilli V,et al. The long run:neuropro- tective effects of physical exercise on adult neurogenesis from youth to old age[J]. Curr Neuropharmacol,2017,15(4):519-533.
[61] Maekawa T,Ogasawara R,Tsutaki A,et al. Electrically evoked local muscle contractions cause an increase in hippocampal BDNF[J]. Ap- pl Physiol Nutr Metab,2018,43(5):491-496.
[62] Saxton RA,Sabatini DM. mTOR signaling in growth,metabolism,and disease[J]. Cell,2017,168(6):960-976.
[63] Lloyd BA,Hake HS,Ishiwata T,et al. Exercise increases mTOR sig- naling in brain regions involved in cognition and emotional behavior[J]. Behav Brain Res,2017,323:56 -67. DOI:10.1016/j.bbr.2017. 01.033.
[64] Elfving B,Christensen T,Ratner C,et al. Transient activation of mTOR following forced treadmill exercise in rats[J]. Synapse,2013, 67(9):620-625.
[65] Victorino AB,Serra FT,Pi觡ero PP,et al. Aerobic exercise in adoles- cence results in an increase of neuronal and non-neuronal cells and in mTOR overexpression in the cerebral cortex of rats [J]. Neuro - science,2017,361:108-115. DOI:10.1016/j.neuroscience.2017.08.002.
[66] Nigam SM,Xu S,Kritikou JS,et al. Exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP[J]. J Neu- rochem,2017,142(2):286-296.
[67] Plummer S,Van den Heuvel C,Thornton E,et al. The neuroprotective properties of the amyloid precursor protein following traumatic brain injury[J].Aging Dis,2016,7(2):163-179.
阿尔兹海默病(Alzheimer’s disease,AD)是一种神经退行性疾病,表现为记忆功能及认知功能的进行性退化,主要的病理特点是 β 淀粉样蛋白沉积及 tau 蛋白过度磷酸化[1]。随着社会老龄化进展及人口寿命的延长,AD 已快速成为全球性问题。尽管针对 AD 的发病机制、诊断治疗已成为全世界的研究热点,但目前仍然缺乏有效的治疗方法。因此,AD 的预防就显得更为重要。越来越多的证据表明,身体活动可能为一种实用、经济,并且可行的预防和改善 AD 的方法。多项研究显示,日常身体活动能降低 AD 的发生风险[2-4]。2019 年哥本哈根共识声明(体力活动与衰老)中也指出,成年期身体活动能减慢或延迟年龄相关的认知功能下降及神经退行性疾病的发生[5]。英国、美国、欧洲一项人群分析显示,在 AD 发病风险因素中,所占比例最大的就是缺乏身体活动[6]。对 AD 患者来说,身体活动也能帮助其改善认知、记忆功能[7-9]。近年来,关于身体活动对AD 的预防及改善作用机制研究也越来越多,越来越深入,本文中就其进行概述,为更加有效地开展早期预防及综合治疗 AD 提供思路及依据。
1 身体活动对机体炎症反应的影响
炎症是 AD 病理生理发生发展的一个重要部分[10]。其中,小胶质细胞激活引起的炎症反应是其中一方面。小胶质细胞占中枢神经系统细胞的 10%,也是大脑免疫系统的主要细胞成分[11]。在衰老、肥胖、系统性炎症、 急性脑损伤早期时,以及 β 淀粉样蛋白沉积达到一定量时,小胶质细胞被激活,激活的小胶质细胞能释放多种炎症因子,如白细胞介素(IL)-1β、肿瘤坏死因子-α(TNF-α)、IL-6 等[11]。Xiong 等[12]使用 APP/PS1 转基因AD 小鼠模型进行研究发现,长期跑台运动能显着减少活化的小胶质细胞,从而显着改善 AD 小鼠的空间学习及记忆功能,但是,对海马区及大脑皮质 Aβ 斑块的沉积没有影响,因此,推测身体活动对空间学习和记忆功能的影响不是 Aβ 斑块减少的结果。低水平的全身炎症反应通常发生于代谢综合征、胰岛素抵抗、高血压、血脂异常及肥胖等疾病[13]。研究发现,超重、肥胖的糖尿病患者血液中炎症因子水平升高,如 IL-1β、IL-6 和 TNF-α 等,而糖尿病与 AD 在病理发生方面有诸多类似的地方,这些炎症因子在 AD 患者大脑、脑脊液及血液中也升高[14-16]。而且,低水平的全身炎症反应会明显影响血脑屏障,使其通透性增加,炎症因子更易穿过,促进大脑胰岛素抵抗,并导致线粒体功能异常及Aβ 沉积[17]。伴随着胰岛素抵抗、脂代谢异常,神经酰胺的产生增加,这类分子也可以穿过血脑屏障,导致炎症反应并干扰大脑胰岛素信号通路[18]。研究发现,身体活动能改善脂代谢异常,从而降低神经酰胺水平,减轻炎症反应[19-20]。此外,骨骼肌作为机体最大的器官,也能产生并释放炎症因子,如 IL-6、IL-8、IL-15 和 TNF-α,它们被称为肌肉因子(myokine)[21]。Handschin 等[22]发现,身体活动能通过上调过氧化物酶体增殖物激活受体-γ 辅助活化因子-1α(PGC -1α)广泛抑制肌肉因子的表达。
2 身体活动对线粒体结构及功能的影响
线粒体对于细胞能量产生、钙平衡的维持及细胞凋亡都非常重要。氧化应激及钙超载会引起线粒体膜通透性转换孔开放,进而激活由线粒体诱导的细胞凋亡[23]。神经系统的线粒体磷酸化系统结构的完整性及功能的维持很大程度上取决于线粒体的氧化还原环境。越来越多的证据表明线粒体功能异常与 AD 相关[24]。Marques-Aleixo 等[25]发现,身体活动能减少氧自由基产生,改善线粒体呼吸活力,增加氧化磷酸化复合体Ⅰ、Ⅲ、Ⅴ亚单位,对钙离子诱导的线粒体膜通透性转换孔开放的抵抗增强。线粒体功能异常与控制线粒体分裂和融合的蛋白失衡相关。由于调控线粒体融合的蛋白 Mfn1、Mfn2 与视神经萎缩蛋白 1(optic atrophy, OPA1) 水平明显下降,AD 患者大脑的线粒体融合减少;相反,发动蛋白相关蛋白 1(dynamin-related protein 1,Drp1)线粒体分裂因子(mitochondrial fission factor,Mff)水平明显升高,表现为线粒体过度分裂[26]。线粒体融合与分裂异常与 AD 患者的树突棘丢失、海马学习与记忆功能受损相关,而身体活动能明显改善线粒体结构和功能。Marques-Aleixo 等[25]发现,身体活动组大鼠线粒体融合相关蛋白 Mfn1、Mfn2 水平升高,线粒体分裂相关蛋白Drp1 水平下降。最近研究发现,APP/PS1转基因 AD 小鼠模型线粒体数目增加、长度明显缩短, 超微结构异常,如线粒体嵴丢失、线粒体肿胀、髓内损害、空泡增加等,同时功能异常,表现为 ATP 水平下降。跑台运动能改善 APP/PS1 转基因 AD 小鼠海马区线粒体超微结构,线粒体数目减少、长度增加,融合增加,分裂受到抑制,产生 ATP 更多,学习、记忆功能明显改善。但是,对于正常野生型小鼠,运动对学习、记忆力及线粒体功能并无明显改善,但可以使受损的功能回归到正常水平,因此,推测增加身体活动能够预防AD 发生并延缓 AD 恶化[27]。3 身体活动与自噬
自噬是被破坏的蛋白质及功能异常的细胞器被溶酶体降解清除,进而维持细胞稳态的过程。自噬功能障碍会明显破坏健康细胞,使 β 淀粉样蛋白沉积增多,导致 AD;相反,自噬功能增强则可以清除 β 淀粉样蛋白,减少其沉积[28]。在自噬过程中,Beclin 1 蛋白参与自噬体的形成,微管相关蛋白轻链 3(LC3-II)调控自噬体的延伸和成熟[29]。p62 是自噬的底物,与 LC3 相互作用,进入自噬体膜内降解,由于不完全降解,较高的p62 水平通常意味着自噬的抑制[30]。溶酶体相关膜蛋白1(Lamp1)是与溶酶体相关的标志性蛋白质。He 等[31]发现,急性运动能升高野生型成年大鼠大脑内 LC3-II 水平,降低 p62 水平,Marques-Aleixo 等[25]发现,长期中等强度运动能显着升高皮质 LC3-II 水平,降低 p62 水平。Zhao 等[32]发现,不活动的 APP/PS1 转基因 AD 小鼠自噬活性明显下降,LC3 -II 与 p62 水平明显升高, Lamp1 明显过表达,表示溶酶体堆积,因而 β 淀粉样斑块明显;运动组 APP/PS1 转基因 AD 小鼠自噬活性增强,p62 与 Lamp1 水平显着下降,β 淀粉样斑块面积缩小;而野生型小鼠运动后,Beclin1、LC3-II、Lamp1 水平也升高,表明运动增强了自噬体形成,使得 β 淀粉样蛋白沉积减少。4 身体活动对大脑血管功能及血流量的影响
随着年龄的增加,血压升高、血管硬化、内皮细胞功能异常,容易出现脑血管功能异常,继而出现大脑局部萎缩、代谢降低,大脑血流量减少,进而导致 AD[33]。对于 AD 患者来说,出现轻度认知损伤还未发展为 AD 时,大脑血流量已经开始减少,发展为 AD 的患者大脑血流量减少约 40%,尤其是楔前叶、海马、扣带回后部血流量减少更加明显[34-36]。身体活动可以通过改善脑血管功能阻止或延缓 AD 的发生。研究发现,身体活动能增加脑血流量,缓解年龄对大脑血流量的影响,改善认知功能[37]。然而,最近的一项研究发现,对轻中度 AD 患者进行中高强度的有氧运动干预 16 周后,大脑整体及局部血流量并无改善,可能由于 AD 症状出现前若干年,就已经存在脑血流灌注量的逐渐减少,而从 AD 症状出现到进展为轻中度,观察到的脑血流量变化已经微乎其微,即脑血流量已相对固定,不易被改变,因此身体活动对其影响不明显,也可能与干预时间较短有关系[38]。因此,关于身体活动对 AD 患者大脑血流量的影响,还要综合考虑年龄、运动强度及干预时间等因素,进行进一步研究。
5 身体活动通过 FNDC5/irisin 蛋白对大脑的影响
FNDC5/irisin 是近年来新发现的一种激素,锻炼时由肌肉释放到机体其他组织。身体活动首先诱导骨骼肌表达 PGC-1α 这一与机体能量代谢相关的转录辅助激活因子,PGC-1α 促进 III 型纤连蛋白结构域包含蛋白 5 (fibronectin type III domain-containing protein 5, FNDC5)的表达,FNDC5 经酶切产生 irisin。irisin 能促进白色脂肪向棕色脂肪转换,并参与调节糖脂代谢[39]。除此之外,研究发现海马区也表达 FNDC5/irisin,尽管比骨骼肌低很多[40-41]。FNDC5/irisin 能调节神经分化、增殖及神经行为,还能减少炎症因子的释放[42]。Lourenco 等[40]发现 AD 患者及 AD 小鼠模型大脑内、脑脊液中FNDC5/irisin 水平明显下降,同时,体内、体外模型发现注射 β 淀粉样寡聚体后,PGC-1α、FNDC5/irisin 蛋白水平均下降,FNDC5/irisin 基因敲除小鼠突触可塑性、记忆受损,而提高 FNDC5/irisin 水平能改善 AD 小鼠模型的突触可塑性和记忆功能。研究还发现,运动能减轻小鼠由于注射 β 淀粉样寡聚体导致的记忆受损和FNDC5/irisin 水平下降,运动后小鼠海马区 FNDC5/irisin 水平升高,能促进脑源性神经营养因子(BDNF)的表达, 而且,肌肉组织释放的 FNDC5/irisin 增加,也可能通过血脑屏障进入大脑发挥作用[40-41]。FNDC5/irisin 改善突触可塑性及记忆的具体机制尚未完全清楚,可能是FNDC5/irisin 激活 G 蛋白偶联受体-cAMP-PKA-CREB 信号途径,参与调节与突出可塑性及记忆形成相关的基因表达[43-44]。FNDC5/irisin 也可能通过激活 ERK1/2 信号通路发挥神经保护作用,因为使用阻断 ERK1/2 信号通路的化学抑制剂后,FNDC5/irisin的神经保护作用减弱[45]。6 身体活动对血脑屏障的影响
血脑屏障对于维持神经系统微环境的稳态至关重要。AD 患者由于氧自由基积累激活金属蛋白酶,氧化型胆固醇堆积,胰岛素信号途径受损,使得血脑屏障的基膜、紧密连接被破坏,导致血脑屏障完整性受损[46]。 大约 70%~85%的 β 淀粉样蛋白的清除都需要经过血脑屏障,血脑屏障功能障碍会影响 β 淀粉样蛋白的清除,炎症因子更容易进入大脑,同时,神经酰胺也能穿过血脑屏障,导致炎症反应,加重神经元功能异常[47]。 规律的身体活动能降低血脑屏障的通透性,增强其抗氧化能力和抗炎效果,改善内皮细胞功能,还可能增加大脑毛细血管的密度,改善缺血[48]。在血脑屏障结构中,紧密连接非常重要,它不同于普通上皮细胞的紧密连接,对微环境更加敏感。大脑内皮细胞间的紧密连接主要由 3 种跨膜蛋白组成:紧密连接蛋白、封闭蛋白和连接相关分子,还有一些胞浆蛋白,如闭锁小带[49]。Souza 等[50]发现,身体活动使得紧密连接复合体蛋白, 如紧密连接蛋白、封闭蛋白-4 的表达重新建立,并抑制血小板内皮细胞黏附分子表达,表明身体活动可以通过保护紧密连接维持血脑屏障的完整性。de Senna 等[51]发现,1 型糖尿病大鼠海马区、纹状体紧密连接蛋白-5 的表达下降,身体活动能保持纹状体紧密连接蛋白-5 的表达,从而影响血脑屏障的结构。然而,He 等[52]发现,身体活动虽然能促进 β 淀粉样蛋白的清除,减少小胶质细胞的活化,但对血脑屏障通透性并无明显影响。色氨酸通过犬尿氨酸(kynurenine,KYN)途径的分解产物也会影响血脑屏障[48]:色氨酸首先在吲哚胺 2,3-双加氧酶(indoeamine 2,3-dioxygenase,IDO)作用下降解为 KYN,KYN 再由犬尿氨酸氨基转移酶(kynurenine aminotransferase,KAT) 代谢为具有神经保护作用的犬尿酸(kynurenic acid,KYNA),或代谢为神经毒性产物,如喹啉酸(quinolinic acid,QUIN)或邻氨基苯甲酸。喹啉酸是 N-甲基-D 天冬氨酸(N-methyl-D-aspartate, NMDA)的选择性激动剂,能诱导氧自由基产生,具有潜在的神经毒性。研究发现,身体活动能促进 KAT 基因的表达,使有毒的 KYN 转化为具有神经保护作用的KYNA,KYNA 对 NMDA 受体有拮抗作用[53]。KYNA 还可以通过降低病理性谷氨酸水平起到保护血脑屏障的作用[54]。7 身体活动对 AD 相关基因及神经营养因子表达的影响
Berchtold 等[55]检测了认知功能正常的年轻人、老年人及 AD 患者的基因,发现即使是晚年开始身体活动也能影响海马区基因表达重排,身体活动组超过70%的抗衰老或 AD 基因表达增加,衰老或 AD 基因表达减少,绝大多数基因参与调控线粒体能量产生、突触可塑性及轴突功能。随着衰老的进展,机体产能逐渐减少,体力活动能增加呼吸电子传递链及三羧酸循环中多种成分的基因表达,促进能量产生。足够的能量对于维持突触正常功能也是非常重要的。同时,身体活动使很多调节突触效能的基因表达增加,如调节突触小泡形成、释放、再摄取的突触前成分,突触后的 γ-氨基丁酸及谷氨酸神经递质受体等。而且,身体活动使得维持髓鞘完整性及轴突功能的相关基因表达增加,并能抵消AD 相关的异常转录,但是未发现身体活动对炎症相关基因的表达有强有力的影响。身体活动也能促进神经营养因子,如 BDNF、胰岛素样生长因子(IGF)和血管内皮生长因子(VEGF)等的表达增加[56-58]。研究发现, 身体活动产生的乳酸也能促进 BDNF 的表达[59]。BDNF 在大脑中高表达,在神经细胞增殖、神经元分化、维持神经元生存及正常生理功能、突触可塑性等方面发挥重要作用。多项研究发现,无论动物模型、健康人群还是轻度认知功能障碍者,身体活动都可以使 BDNF 表达增加,而且它能通过血脑屏障进入大脑[12,55-56,60]。即使无意识状态下的肌肉收缩也能使海马区 BDNF 表达增加[61]。BDNF 可以与原肌球蛋白激酶 B 受体结合,启动磷酸化级联反应, 激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路,该信号通路在调节神经细胞突触可塑性、自噬等方面发挥重要作用[62]。然而,身体活动对 mTOR 信号通路的影响目前研究结果尚未一致。研究发现,身体活动后,大脑许多区域如海马区、前额叶皮质、纹状体、下丘脑等部位 mTOR 磷酸化水平增加,有的研究发现,身体活动后,皮质区 mTOR 表达增加,但海马区无变化,也有研究发现身体活动后 24 h,mTOR 有短暂的表达增加,之后并未增加[63-65]。此外,BDNF 促进 α 分泌酶重新分布,裂解 β 淀粉样前体蛋白成为分泌型 α 分泌酶裂解的淀粉样前体蛋白细胞外片段(sAPPα),从而减少 β 淀粉样蛋白的产生[66]。研究发现,sAPPα 具有神经保护及神经营养功能,并可促进神经发生及突触可塑性[67]。
身体活动对 AD 的预防及改善作用机制研究日益深入,尽管有些研究结果不尽相同,但身体活动对 AD 的效果却受到越来越多研究者的认可,无论是预防还是改善 AD,身体活动在其中的作用都将会更加受到重视。未来,随着作用机制研究的不断深入,以及不同人群、不同运动方式、运动时间及运动强度方面长期大样本人群研究的开展,我们将进一步明确身体活动对 AD 的意义。
参考文献
[1] Murman DL. The impact of age on cognition[J]. Semin Hear,2015, 36(3):111-121.
[2] Beckett MW,Ardern CI,Rotondi MA. A meta-analysis of prospective studies on the role of physical activity and the prevention of Alzheimer ’s disease in older adults[J]. BMC Geriatr,2015,15:9. DOI:10.1186/s12877-015-0007-2.
[3] Beydoun MA,Beydoun HA,Gamaldo AA,et al. Epidemiologic stud- ies of modifiable factors associated with cognition and dementia:sys-tematic review and meta-analysis[J]. BMC Public Health,2014,14(643):1-33.
[4] Hamer M,Chida Y. Physical activity and risk of neurodegenerative disease:a systematic review of prospective evidence[J]. Psychol Med, 2009,39(1):3-11.
[5] Bangsbo J,Blackwell J,Boraxbekk CJ,et al. Copenhagen consensus statement 2019:physical activity and ageing[J]. Br J Sports Med, 2019,53(14):856-858.
[6] Norton S,Matthews FE,Barnes DE,et al. Potential for primary prevention of Alzheimer’s disease:an analysis of population -based data[J]. Lancet Neurol,2014,13(8):788-794.
[7] Ginis KA,Heisz J,Spence JC,et al. Formulation of evidence -based messages to promote the use of physical activity to prevent and man- age Alzheimer's disease[J]. BMC Public Health,2017,17(1):209. DOI:10.1186/s12889-017-4090-5.
[8] Stubbs B,Chen LJ,Chang CY,et al. Accelerometer -assessed light physical activity is protective of future cognitive ability:a longitudinal study among community dwelling older adults[J]. Exp Gerontol, 2017,91:104-109. DOI:10.1016/j.exger.2017.03.003.
[9] Suwabe K,Byun K,Hyodo K,et al. Rapid stimulation of human den- tate gyrus function with acute mild exercise[J]. Proc Natl Acad Sci U S A,2018,115(41):10487-10492.
[10] Calsolaro V,Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions[J]. Alzheimers Dement, 2016,12(6):719-732.
[11] Tejera D,Heneka MT. Microglia in Alzheimer's disease:the good,the bad and the ugly[J]. Curr Alzheimer Res,2016,13(4):370-380.
[12] Xiong JY,Li SC,Sun YX,et al. Long -term treadmill exercise im- proves spatial memory of male APPswe/PS1dE9 mice by regulation of BDNF expression and microglia activation[J]. Biol Sport,2015,32(4):295-300.
[13] León-Pedroza JI,González -Tapia LA,del Olmo-Gil E,et al. Low- grade systemic inflammation and the development of metabolic dis - eases:from the molecular evidence to the clinical practice[J]. Cir Cir, 2015,83(6):543-551.
[14] Reinehr T,Karges B,Meissner T,et al. Inflammatory markers in obese adolescents with type 2 diabetes and their relationship to hepa- tokines and adipokines[J]. J Pediatr,2016,173:131 -135. DOI: 10.1016/j.jpeds.2016.02.055.
[15] Rajkovic N,Zamaklar M,Lalic K,et al. Relationship between obesi- ty,adipocytokines and inflammatory markers in type 2 diabetes:rele- vance for cardiovascular risk prevention[J]. Int J Environ Res Public Health,2014,11(4):4049-4065.
[16] Gironès X,Guimerà A,Cruz -Sánchez CZ,et al. N epsilon -car- boxymethyllysine in brain aging,diabetes mellitus,and Alzheimer's disease[J]. Free Radic Biol Med,2004,36(10):1241-1247.
[17] Grimm A,Friedland K,Eckert A. Mitochondrial dysfunction:the missing link between aging and sporadic Alzheimer's disease[J]. Biogerontology,2016,17(2):281-296.
[18] De la Monte SM. Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides,ER stress,and insulin resistance re- viewed[J]. J Alzheimers Dis,2012,30(Suppl 2):S231-249.
[19] Dubé JJ,Amati F,Toledo FG,et al. Effects of weight loss and exercise on insulin resistance,and intramyocellular triacylglycerol,diacylglyc- erol and ceramide[J]. Diabetologia,2011,54(5):1147-1156.
[20] Kasumov T,Solomon TP,Hwang C. Improved insulin sensitivity after exercise training is linked to reduced plasma C14:0 ceramide in obe- sity and type 2 diabetes[J]. Obesity(Silver Spring),2015,23(7): 1414-1421.
[21] Pedersen BK. Muscles and their myokines[J]. J Exp Biol,2011,214(Pt 2):337-346.
[22] Handschin C,Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease[J]. Nature,2008,454(7203):463- 469.
[23] Toman J,Fiskum G. Influence of aging on membrane permeability transition in brain mitochondria[J]. J Bioenerg Biomembr,2011,43(1):3-10.
[24] Spuch C,Ortolano S,Navarro C. New insights in the amyloid -Beta interaction with mitochondria[J]. J Aging Res,2012,2012:324968. DOI:10.1155/2012/324968.
[25] Marques -Aleixo I,Santos -Alves E,Bal觭a MM,et al. Physical exer- cise improves brain cortex and cerebellum mitochondrial bioenerget- ics and alters apoptotic,dynamic and auto (mito)phagy markers[J]. Neuroscience,2015,301:480 -495. DOI:10.1016/j.neuroscience.2015. 06.027.
[26] Wang X,Su B,Lee HG,et al. Impaired balance of mitochondrial fis- sion and fusion in Alzheimer's disease[J]. J Neurosci,2009,29(28): 9090-9103.
[27] Yan QW,Zhao N,Xia J,et al. Effects of treadmill exercise on mito- chondrial fusion and fission in the hippocampus of APP/PS1 mice[J]. Neurosci Lett,2019,701:84-91. DOI:10.1016/j.neulet.2019.02.030.
[28] Jiang T,Yu JT,Zhu XC. Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease[J]. Pharmacol Res,2014,81:54-63. DOI:10.1016/j.phrs.2014.02.008.
[29] McKnight NC,Zhenyu Y. Beclin 1,an essential component and mas- ter regulator of PI3K-III in health and disease[J]. Curr Pathobiol Rep,2013,1(4):231-238.
[30] Johansen T,Lamark T. Selective autophagy mediated by autophagic adapter proteins[J]. Autophagy,2011,7(3):279-296.
[31] He C,Sumpter R Jr,Levine B. Exercise induces autophagy in periph- eral tissues and in the brain[J]. Autophagy,2012,8(10):1548-1551.
[32] Zhao N,Zhang X,Song C. The effects of treadmill exercise on au - tophagy in hippocampus of APP/PS1 transgenic mice[J]. Neurore- port,2018,29(10):819-825.
[33] Barnes JN,Corkery AT. Exercise improves vascular function,but does this translate to the brain?[J]. Brain Plast,2018,4(1):65-79.
[34] Asllani I,Habeck C,Scarmeas N,et al. Multivariate and univariate analysis of continuous arterial spin labeling perfusion MRI in Alzheimer's disease[J]. J Cereb Blood Flow Metab,2008,28(4): 725-736.
[35] Binnewijzend MA,Kuijer JP,Benedictus MR,et al. Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment:a mark- er for disease severity[J]. Radiology,2013,267(1):221-230.
[36] Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration,cogni- tive impairment,and Alzheimer's disease[J]. J Neurosci Res,2017, 95(4):943-972.
[37] Lucas SJ,Ainslie PN,Murrell CJ,et al. Effect of age on exercise-in- duced alterations in cognitive executive function:relationship to cere- bral perfusion[J]. Exp Gerontol,2012,47(8):541-551.
[38] Van der Kleij LA,Petersen ET,Siebner HR. The effect of physical exercise on cerebral blood flow in Alzheimer's disease[J]. Neuroim- age Clin,2018,20:650-654. DOI:10.1016/j.nicl.2018.09.003.
[39] Bostr觟m P,Wu J,Jedrychowski MP,et al. A PGC1 -α -dependent myokine that drives brown-fat-like development of white fat and ther- mogenesis[J]. Nature,2012,481(7382):463-468.
[40] Lourenco MV,Frozza RL,de Freitas GB. Exercise -linked FNDC5/ irisin rescues synaptic plasticity and memory defects in Alzheimer's models[J]. Nat Med,2019,25(1):165-175.
[41] Wrann CD,White JP,Salogiannnis J,et al. Exercise induces hip-
pocampal BDNF through a PGC-1α/FNDC5 pathway[J]. Cell Metab, 2013,18(5):649-659.
[42] Zhang J,Zhang W. Can irisin be a linker between physical activity and brain function?[J]. Biomol Concepts,2016,7(4):253-258.
[43] Benito E,Barco A. CREB's control of intrinsic and synaptic plastici - ty :implications for CREB - dependent memory models[J]. Trends Neurosci,2010,33(5):230-240.
[44] Chen X,Gan L. An exercise -induced messenger boosts memory in Alzheimer's disease[J]. Nat Med,2019,25(1):20-21.
[45] Li DJ,Li YH,Yuan HB,et al. The novel exercise-induced hormone
irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia[J]. Metabolism,2017,68:31- 42. DOI:10.1016/j.metabol.2016.12.003.
[46] Gamba P,Testa G,Gargiulo S,et al. Oxidized cholesterol as the driv-ing force behind the development of Alzheimer's disease[J]. Front Aging Neurosci,2015,7:119. DOI:10.3389/fnagi.2015.00119.
[47] Zhao Z,Nelson AR,Betsholtz C,et al. Establishment and dysfunction of the blood-brain barrie[r J]. Cell,2015,163(5):1064-1078.
[48] Ma覥kiewicz MA,Szarmach A,Sabisz A,et al. Blood -brain barrier permeability and physical exercise[J]. J Neuroinflammation,2019, 16(1):15. DOI:10.1186/s12974-019-1403-x.
[49] Wolburg H,Lippoldt A. Tight junctions of the blood -brain barrier: development,composition and regulation[J]. Vascul Pharmacol,2002, 38(6):323-337.
[50] Souza PS,Gon觭alves ED,Pedroso GS,et al. Physical exercise attenu- ates experimental autoimmune encephalomyelitis by inhibiting pe- ripheral immune response and blood-brain barrier disruption[J]. Mol Neurobiol,2017,54(6):4723-4737.
[51] de Senna PN,Xavier LL,Bagatini PB,et al. Physical training im- proves non-spatial memory,locomotor skills and the blood brain bar- rier in diabetic rats[J]. Brain Res,2015,1618:75-82. DOI:10.1016/ j.brainres.2015.05.026.
[52] He XF,Liu DX,Zhang Q. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice[J]. Front Mol Neurosci,2017,10:144. DOI: 10.3389/fnmol.2017.00144.
[53] Schlittler M,Goiny M,Agudelo LZ,et al. Endurance exercise increas- es skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans[J]. Am J Physiol Cell Physiol,2016,310(10):C836-840.
[54] Konradsson -Geuken A,Wu HQ,Gash CR,et al. Cortical kynurenic acid bi -directionally modulates prefrontal glutamate levels as as- sessed by microdialysis and rapid electrochemistry[J]. Neuroscience, 2010,169(4):1848-1859.
[55] Berchtold NC,Prieto GA,Phelan M,et al. Hippocampal gene expres- sion patterns linked to late-life physical activity oppose age and AD- related transcriptional decline[J]. Neurobiol Aging,2019,78:142- 154. DOI:10.1016/j.neurobiolaging.2019.02.012.
[56] Tsai CL,Pai MC,Ukropec J,et al. Distinctive effects of aerobic and resistance exercise modes on neurocognitive and biochemical changes in individuals with mild cognitive impairment[J]. Curr Alzheimer Res,2019,16(4):316-332.
[57] Rosa JM,Pazini FL,Olescowicz G,et al. Prophylactic effect of physi- cal exercise on Aβ1 -40 -induced depressive -like behavior:role of BDNF,mTOR signaling,cell proliferation and survival in the hip - pocampus[J]. Prog Neuropsychopharmacol Biol Psychiatry ,2019, 94:109646. DOI:10.1016/j.pnpbp.2019.109646.
[58] E L,Burns JM,Swerdlow RH. Effect of high -intensity exercise on aged mouse brain mitochondria,neurogenesis,and inflammation[J]. Neurobiol Aging,2014,35(11):2574-2583.
[59] Schiffer T,Schulte S,Sperlich B,et al. Lactate infusion at rest in - creases BDNF blood concentration in humans[J].Neurosci Lett, 2011,488(3):234-237.
[60] Saraulli D,Costanzi M,Mastrorilli V,et al. The long run:neuropro- tective effects of physical exercise on adult neurogenesis from youth to old age[J]. Curr Neuropharmacol,2017,15(4):519-533.
[61] Maekawa T,Ogasawara R,Tsutaki A,et al. Electrically evoked local muscle contractions cause an increase in hippocampal BDNF[J]. Ap- pl Physiol Nutr Metab,2018,43(5):491-496.
[62] Saxton RA,Sabatini DM. mTOR signaling in growth,metabolism,and disease[J]. Cell,2017,168(6):960-976.
[63] Lloyd BA,Hake HS,Ishiwata T,et al. Exercise increases mTOR sig- naling in brain regions involved in cognition and emotional behavior[J]. Behav Brain Res,2017,323:56 -67. DOI:10.1016/j.bbr.2017. 01.033.
[64] Elfving B,Christensen T,Ratner C,et al. Transient activation of mTOR following forced treadmill exercise in rats[J]. Synapse,2013, 67(9):620-625.
[65] Victorino AB,Serra FT,Pi觡ero PP,et al. Aerobic exercise in adoles- cence results in an increase of neuronal and non-neuronal cells and in mTOR overexpression in the cerebral cortex of rats [J]. Neuro - science,2017,361:108-115. DOI:10.1016/j.neuroscience.2017.08.002.
[66] Nigam SM,Xu S,Kritikou JS,et al. Exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP[J]. J Neu- rochem,2017,142(2):286-296.
[67] Plummer S,Van den Heuvel C,Thornton E,et al. The neuroprotective properties of the amyloid precursor protein following traumatic brain injury[J].Aging Dis,2016,7(2):163-179.