Neurochemical Research

, Volume 43, Issue 8, pp 1561–1574 | Cite as

Treadmill Exercise Ameliorates Spatial Learning and Memory Deficits Through Improving the Clearance of Peripheral and Central Amyloid-Beta Levels

  • Davar Khodadadi
  • Reza GharakhanlouEmail author
  • Naser Naghdi
  • Mona Salimi
  • Mohammad Azimi
  • Atabak Shahed
  • Soomaayeh Heysieattalab
Original Paper


Aggregated amyloid beta (Aβ) peptides are believed to play a decisive role in the pathology of Alzheimer’s disease (AD). Previous evidence suggested that exercise contributes to the improvement of cognitive decline and slows down pathogenesis of AD; however, the exact mechanisms for this have not been fully understood. Here, we evaluated the effect of a 4-week moderate treadmill exercise on spatial memory via central and peripheral Aβ clearance mechanisms following developed AD-like neuropathology induced by intra-hippocampal Aβ1–42 injection in male Wistar rats. We found Aβ1–42-treated animals showed spatial learning and memory impairment which was accompanied by increased levels of amyloid plaque load and soluble Aβ1–42 (sAβ1–42), decreased mRNA and protein expression of neprilysin (NEP), insulin degrading enzyme (IDE) and low-density lipoprotein receptor-related protein-1 (LRP-1) in the hippocampus. Aβ1–42-treated animals also exhibited a higher level of sAβ1–42 and a lower level of soluble LRP-1 (sLRP-1) in plasma, as well as a decreased level of LRP-1 mRNA and protein content in the liver. However, exercise training improved the spatial learning and memory deficits, reduced both plaque load and sAβ1–42 levels, and up-regulated expression of NEP, IDE, and LRP-1 in the hippocampus of Aβ1–42-treated animals. Aβ1–42-treated animals subjected to treadmill exercise also revealed decreased levels of sAβ1–42 and increased levels of sLRP-1 in plasma, as well as increased levels of LRP-1 mRNA and protein in the liver. In conclusion, our findings suggest that exercise-induced improvement in both of central and peripheral Aβ clearance are likely involved in ameliorating spatial learning and memory deficits in an animal model of AD. Future studies need to determine their relative contribution.


Alzheimer’s disease Spatial learning and memory Treadmill exercise Aβ NEP IDE LRP-1 


  1. 1.
    Musiek ES, Holtzman DM (2015) Three dimensions of the amyloid hypothesis: time, space and’wingmen’. Nat Neurosci 18(6):800–806CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766CrossRefPubMedGoogle Scholar
  3. 3.
    Palop JJ, Mucke L (2010) Amyloid-[beta]-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zolezzi JM, Bastías-Candia S, Santos MJ, Inestrosa NC (2014) Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs. Front Aging Neurosci 6:176CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330:1774–1774CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rolyan H, Feike AC, Upadhaya AR, Waha A, Van Dooren T, Haass C, Birkenmeier G, Pietrzik CU, Van Leuven F, Thal DR (2011) Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer’s disease. J Neural Transm 118:699–712CrossRefPubMedGoogle Scholar
  7. 7.
    Nalivaeva NN, Belyaev ND, Kerridge C, Turner AJ (2014) Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease. Front Aging Neurosci 6:235CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain. J Clin Investig 118:4002CrossRefPubMedGoogle Scholar
  9. 9.
    Sagare AP, Deane R, Zlokovic BV (2012) Low-density lipoprotein receptor-related protein 1: a physiological Aβ homeostatic mechanism with multiple therapeutic opportunities. Pharmacol Ther 136:94–105CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Erdő F, Denes L, de Lange E (2017) Age-associated physiological and pathological changes at the blood–brain barrier: a review. J Cereb Blood Flow Metab 37:4–24CrossRefPubMedGoogle Scholar
  12. 12.
    Mohamed LA, Qosa H, Kaddoumi A (2015) Age-related decline in brain and hepatic clearance of amyloid-beta is rectified by the cholinesterase inhibitors donepezil and rivastigmine in rats. ACS Chem Neurosci 6:725–736CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yasojima K, Akiyama H, McGeer EG, McGeer PL (2001) Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of β-amyloid peptide. Neurosci Lett 297:97–100CrossRefPubMedGoogle Scholar
  14. 14.
    Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T (2007) Clearance of amyloid-β by circulating lipoprotein receptors. Nat Med 13:1029–1031CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, Khanna P, Jain SC, Thakur SS, Ravindranath V (2012) Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci 109:3510–3515CrossRefPubMedGoogle Scholar
  16. 16.
    Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 9:58–65CrossRefPubMedGoogle Scholar
  17. 17.
    Luck T, Riedel-Heller S, Luppa M, Wiese B, Köhler M, Jessen F, Bickel H, Weyerer S, Pentzek M, König H-H (2014) Apolipoprotein E epsilon 4 genotype and a physically active lifestyle in late life: analysis of gene–environment interaction for the risk of dementia and Alzheimer’s disease dementia. Psychol Med 44:1319–1329CrossRefPubMedGoogle Scholar
  18. 18.
    Moore KM, Girens RE, Larson SK, Jones MR, Restivo JL, Holtzman DM, Cirrito JR, Yuede CM, Zimmerman SD, Timson BF (2016) A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer’s disease. Neurobiol Dis 85:218–224CrossRefPubMedGoogle Scholar
  19. 19.
    Maliszewska-Cyna E, Xhima K, Aubert I (2016) A comparative study evaluating the impact of physical exercise on disease progression in a mouse model of Alzheimer’s disease. J Alzheimers Dis 53:243–257CrossRefPubMedGoogle Scholar
  20. 20.
    Parachikova A, Nichol K, Cotman C (2008) Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 30:121–129CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yuede CM, Zimmerman SD, Dong H, Kling MJ, Bero AW, Holtzman DM, Timson BF, Csernansky JG (2009) Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis 35:426–432CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Roberts KF, Elbert DL, Kasten TP, Patterson BW, Sigurdson WC, Connors RE, Ovod V, Munsell LY, Mawuenyega KG, Miller-Thomas MM (2014) Amyloid-β efflux from the central nervous system into the plasma. Ann Neurol 76:837–844CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Tamaki C, Ohtsuki S, Terasaki T (2007) Insulin facilitates the hepatic clearance of plasma amyloid β-peptide (1–40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes. Mol Pharmacol 72:850–855CrossRefPubMedGoogle Scholar
  24. 24.
    Mackic JB, Bading J, Ghiso J, Walker L, Wisniewski T, Frangione B, Zlokovic BV (2002) Circulating amyloid-β peptide crosses the blood–brain barrier in aged monkeys and contributes to Alzheimer’s disease lesions. Vascul Pharmacol 38:303–313CrossRefPubMedGoogle Scholar
  25. 25.
    Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, Head D (2010) Exercise and Alzheimer’s disease biomarkers in cognitively normal older adults. Ann Neurol 68:311–318CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, Holtzman DM, Morris JC (2012) Exercise engagement as a moderator of the effects of APOE genotype on amyloid deposition. Arch Neurol 69:636–643CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Brown B, Peiffer J, Taddei K, Lui J, Laws S, Gupta VB, Taddei T, Ward V, Rodrigues M, Burnham S (2013) Physical activity and amyloid-β plasma and brain levels: results from the Australian imaging, biomarkers and lifestyle study of ageing. Mol Psychiatry 18:875–881CrossRefPubMedGoogle Scholar
  28. 28.
    García-Mesa Y, López-Ramos JC, Giménez-Llort L, Revilla S, Guerra R, Gruart A, LaFerla FM, Cristòfol R, Delgado-García JM, Sanfeliu C (2011) Physical exercise protects against Alzheimer’s disease in 3xTg-AD mice. J Alzheimers Dis 24:421–454CrossRefPubMedGoogle Scholar
  29. 29.
    Maesako M, Uemura K, Kubota M, Kuzuya A, Sasaki K, Hayashida N, Asada-Utsugi M, Watanabe K, Uemura M, Kihara T (2012) Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice. J Biol Chem 287:23024–23033CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wolf SA, Kronenberg G, Lehmann K, Blankenship A, Overall R, Staufenbiel M, Kempermann G (2006) Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biol Psychiatry 60:1314–1323CrossRefPubMedGoogle Scholar
  31. 31.
    Richter H, Ambrée O, Lewejohann L, Herring A, Keyvani K, Paulus W, Palme R, Touma C, Schäbitz W-R, Sachser N (2008) Wheel-running in a transgenic mouse model of Alzheimer’s disease: protection or symptom? Behav Brain Res 190:74–84CrossRefPubMedGoogle Scholar
  32. 32.
    Xu ZQ, Zhang LQ, Wang Q, Marshall C, Xiao N, Gao JY, Wu T, Ding J, Hu G, Xiao M (2013) Aerobic exercise combined with antioxidative treatment does not counteract moderate-or mid-stage Alzheimer-like pathophysiology of APP/PS1 mice. CNS Neurosci Ther 19:795–803PubMedGoogle Scholar
  33. 33.
    Becker JA, Hedden T, Carmasin J, Maye J, Rentz DM, Putcha D, Fischl B, Greve DN, Marshall GA, Salloway S (2011) Amyloid-β associated cortical thinning in clinically normal elderly. Ann Neurol 69:1032–1042CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yan JJ, Cho JY, Kim HS, Kim KL, Jung JS, Huh SO, Suh HW, Kim YH, Song DK (2001) Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol 133:89–96CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Prakash A, Medhi B, Chopra K (2013) Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-β induced experimental model of Alzheimer’s disease. Pharmacol Biochem Behav 110:46–57CrossRefPubMedGoogle Scholar
  36. 36.
    Mohammadpour JD, Hosseinmardi N, Janahmadi M, Fathollahi Y, Motamedi F, Rohampour K (2015) Non-selective NSAIDs improve the amyloid-β-mediated suppression of memory and synaptic plasticity. Pharmacol Biochem Behav 132:33–41CrossRefGoogle Scholar
  37. 37.
    Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, San DiegoGoogle Scholar
  38. 38.
    Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, Alkadhi K (2012) The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Dis 45:1153–1162CrossRefPubMedGoogle Scholar
  39. 39.
    Dao AT, Zagaar MA, Alkadhi KA (2015) Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease. Mol Neurobiol 52:1067–1076CrossRefPubMedGoogle Scholar
  40. 40.
    Dao AT, Zagaar MA, Levine AT, Salim S, Eriksen JL, Alkadhi KA (2013) Treadmill exercise prevents learning and memory impairment in Alzheimer’s disease-like pathology. Curr Alzheimer Res 10:507–515CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Heysieattalab S, Naghdi N, Zarrindast M-R, Haghparast A, Mehr SE, Khoshbouei H (2016) The effects of GABAA and NMDA receptors in the shell–accumbens on spatial memory of METH-treated rats. Pharmacol Biochem Behav 142:23–35CrossRefPubMedGoogle Scholar
  42. 42.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2–∆∆CT method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  43. 43.
    Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N, Rastegar K, Moosavi M (2010) Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis. Eur J Pharmacol 634:84–88CrossRefPubMedGoogle Scholar
  44. 44.
    Tang S-S, Ji M-j, Chen L, Hu M, Long Y, Li Y-q, Miao M-x, Li J-c, Li N, Ji H (2014) Protective effect of pranlukast on A β 1–42-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1. Int J Neuropsychopharmacol 17:581–592CrossRefPubMedGoogle Scholar
  45. 45.
    Wang R, Zhang Y, Li J, Zhang C (2017) Resveratrol ameliorates spatial learning memory impairment induced by Aβ1–42 in rats. Neuroscience 344:39–47CrossRefPubMedGoogle Scholar
  46. 46.
    Zhang L, Fang Y, Xu Y, Lian Y, Xie N, Wu T, Zhang H, Sun L, Zhang R, Wang Z (2015) Curcumin improves amyloid β-peptide (1–42) induced spatial memory deficits through BDNF-ERK signaling pathway. PLoS One 10:e0131525CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhang L, Fang Y, Lian Y, Chen Y, Wu T, Zheng Y, Zong H, Sun L, Zhang R, Wang Z (2015) Brain-derived neurotrophic factor ameliorates learning deficits in a rat model of Alzheimer’s disease induced by aβ1–42. PLoS ONE 10:e0122415CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ali T, Yoon GH, Shah SA, Lee HY, Kim MO (2015) Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep 5:11708CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Sharma S, Verma S, Kapoor M, Saini A, Nehru B (2016) Alzheimer’s disease like pathology induced six weeks after aggregated amyloid-beta injection in rats: increased oxidative stress and impaired long-term memory with anxiety-like behavior. Neurol Res 38:838–850CrossRefPubMedGoogle Scholar
  50. 50.
    Baleriola J, Walker CA, Jean YY, Crary JF, Troy CM, Nagy PL, Hengst U (2014) Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell 158:1159–1172CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) β-Amyloid1–42 induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28:3941–3946CrossRefPubMedGoogle Scholar
  52. 52.
    Jean YY, Baleriola J, Fà M, Hengst U, Troy CM (2015) Stereotaxic infusion of oligomeric amyloid-beta into the mouse hippocampus. J Vis Exp. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Faucher P, Mons N, Micheau J, Louis C, Beracochea DJ (2016) Hippocampal injections of oligomeric amyloid β-peptide (1–42) induce selective working memory deficits and long-lasting alterations of ERK signaling pathway. Front Aging Neurosci 7:245CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Yue X-H, Tong J-Q, Wang Z-J, Zhang J, Liu X, Liu X-J, Cai H-Y, Qi J-S (2016) Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid β protein in male rats. Hormon Behav 83:83–92CrossRefGoogle Scholar
  55. 55.
    Wu L, Feng X, Li T, Sun B, Khan MZ, He L (2017) Risperidone ameliorated Aβ 1-42-induced cognitive and hippocampal synaptic impairments in mice. Behav Brain Res 322:145–156CrossRefPubMedGoogle Scholar
  56. 56.
    Young J, Angevaren M, Rusted J, Tabet N (2015) Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. CrossRefPubMedGoogle Scholar
  57. 57.
    Morris JK, Vidoni ED, Johnson DK, Van Sciver A, Mahnken JD, Honea RA, Wilkins HM, Brooks WM, Billinger SA, Swerdlow RH (2017) Aerobic exercise for Alzheimer’s disease: a randomized controlled pilot trial. PLoS ONE 12:e0170547CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S (2018) Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway. Peptides. PubMedCrossRefGoogle Scholar
  59. 59.
    Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539CrossRefPubMedGoogle Scholar
  60. 60.
    Adlard PA, Perreau VM, Pop V, Cotman CW (2005) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci 25:4217–4221CrossRefPubMedGoogle Scholar
  61. 61.
    Cho J, Shin M-K, Kim D, Lee I, Kim S, Kang H (2015) Treadmill running reverses cognitive declines due to Alzheimer disease. Med Sci Sports Exerc 47:1814–1824CrossRefPubMedGoogle Scholar
  62. 62.
    Zhao G, Liu H, Zhang H, Tong X (2015) Treadmill exercise enhances synaptic plasticity, but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice. Neuroscience 298:357–366CrossRefPubMedGoogle Scholar
  63. 63.
    Pozueta J, Lefort R, Shelanski M (2013) Synaptic changes in Alzheimer’s disease and its models. Neuroscience 251:51–65CrossRefPubMedGoogle Scholar
  64. 64.
    Schmid AW, Freir DB, Herron CE (2008) Inhibition of LTP in vivo by beta-amyloid peptide in different conformational states. Brain Res 1197:135–142CrossRefPubMedGoogle Scholar
  65. 65.
    McConlogue L, Buttini M, Anderson JP, Brigham EF, Chen KS, Freedman SB, Games D, Johnson-Wood K, Lee M, Zeller M (2007) Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282:26326–26334CrossRefPubMedGoogle Scholar
  66. 66.
    Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee J-M, Holtzman DM (2011) Neuronal activity regulates the regional vulnerability to amyloid-[beta] deposition. Nature Neurosci 14:750–756CrossRefPubMedGoogle Scholar
  67. 67.
    Jha NK, Jha SK, Kumar D, Kejriwal N, Sharma R, Ambasta RK, Kumar P (2015) Impact of insulin degrading enzyme and neprilysin in Alzheimer’s disease biology: characterization of putative cognates for therapeutic applications. J Alzheimers Dis 48:891–917CrossRefPubMedGoogle Scholar
  68. 68.
    Kinni H, Guo M, Ding JY, Konakondla S, Dornbos D III, Tran R, Guthikonda M, Ding Y (2011) Cerebral metabolism after forced or voluntary physical exercise. Brain Res 1388:48–55CrossRefPubMedGoogle Scholar
  69. 69.
    Leasure J, Jones M (2008) Forced and voluntary exercise differentially affect brain and behavior. Neuroscience 156:456–465CrossRefPubMedGoogle Scholar
  70. 70.
    Liu YF, Chen H, Wu CL, Kuo YM, Yu L, Huang AM, Wu FS, Chuang JI, Jen CJ (2009) Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. J Physiol 587:3221–3231CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kurauti MA, Costa-Júnior JM, Ferreira SM, Santos GJ, Sponton CH, Carneiro EM, Telles GD, Chacon-Mikahil MP, Cavaglieri CR, Rezende LF (2017) Interleukin-6 increases the expression and activity of insulin-degrading enzyme. Sci Rep 7:46750CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Kim MS, Goo JS, Kim JE, Nam SH, Choi SI, Lee HR, Hwang IS, Shim SB, Jee SW, Lee SH (2011) Overexpression of insulin degrading enzyme could greatly contribute to insulin down-regulation induced by short-term swimming exercise. Lab Anim Res 27:29–36CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Lin T-W, Shih Y-H, Chen S-J, Lien C-H, Chang C-Y, Huang T-Y, Chen S-H, Jen CJ, Kuo Y-M (2015) Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer’s disease (APP/PS1) transgenic mice. Neurobiol Learn Mem 118:189–197CrossRefPubMedGoogle Scholar
  74. 74.
    Donahue JE, Flaherty SL, Johanson CE, Duncan JA, Silverberg GD, Miller MC, Tavares R, Yang W, Wu Q, Sabo E (2006) RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol 112:405–415CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Davar Khodadadi
    • 1
  • Reza Gharakhanlou
    • 1
    Email author
  • Naser Naghdi
    • 2
  • Mona Salimi
    • 2
  • Mohammad Azimi
    • 1
  • Atabak Shahed
    • 3
  • Soomaayeh Heysieattalab
    • 4
  1. 1.Department of Physical Education and Sport Sciences, Faculty of HumanitiesTarbiat Modares UniversityTehranIran
  2. 2.Department of Physiology and PharmacologyPasteur Institute of IranTehranIran
  3. 3.School of Physical Education and Sport SciencesUniversity of TehranTehranIran
  4. 4.Cognitive Neuroscience Division, Faculty of Education and PsychologyUniversity of TabrizTabrizIran

Personalised recommendations