The Effect of Eight Weeks of Aerobic Training on Some Factors Involved in Cholesterol Metabolism in the Hippocampus and Its Role in Improving the Cognitive Function of Male Wistar Rats

Document Type : Research Paper

Authors
Zahra Sarlak 1
Mahtab Moazami 2
Seyed Reza Attaezade Hosseini 3
Reza Gharakhanloo 4
1 Ph.D. Student in Exercise Physiology, Ferdowsi University of Mashhad
2 Associate Professor of Exercise Physiology, Ferdowsi University of Mashhad
3 Professor of Exercise Physiology, Ferdowsi University of Mashhad
4 Professor of Exercise Physiology, Tarbiat Modares University
10.22089/spj.2018.5319.1705
Abstract
Although the metabolism of blood lipids has been widely considered in studies, lipid metabolism in the brain has attracted more attention in recent years due to its association with some neurological disorders. Recent studies have shown that a number of risk factors for early onset of Alzheimer's are associated with cholesterol metabolism. Therefore, the purpose of this study was to investigate the effect of eight weeks of aerobic training on some factors involved in the metabolism of cholesterol in the hippocampus and its role in improving the cognitive function of male Wistar rats. The subjects of this study were 26 adult male Wistar 8 weeks old (weight 195±20 g). At first, they were randomly divided into two groups: exercise (training on treadmill, 5 days a week for 8 weeks) (13 rats) and control (13 rats). After 8 weeks, the rats in each group were randomly assigned to two other subgroups: (7 rats: behavioral test, 5 rats were sacrificed). The results of one-way ANOVA of Morris water maze showed a significant improvement in learning (P<0.05) and memory (P<0.05) in the exercise group compared to the control group. Also, the results of one-way ANOVA showed a significant increase in the expression of mRNA APOE (P<0.05) and ABCA1 (P<0.05) and no significant difference in the level of Aβ1-42 (P>0.05) in the hippocampus in exercise group compared to the control group. Therefore, aerobic training by a significant increase in the expression of mRNA APOE and ABCA1, which are the main factors of lipid metabolism in the brain and which are involved in the pathology of Alzheimer's disease, can be consistent with improving cognitive function as an effective way of preventing of Alzheimer's disease.
Keywords
Aerobic Training
Cognitive Function
ABCA1
APOE
soluble Aβ1-42

Main Subjects

  1. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001;12(2):105-12.
  2. Kimj J, Yoon H, Horie T, Burchett JM, Restivo JL, Rotllan N, et ail. MicroRNA-33 regulates ApoE lipidation and Amyloid-β metabolism in the brain. J Neurosci. 2015;35(44):14717–26.
  3. Hottman DA, Chernick D, Cheng S, Wang Z, Li L. HDL and cognition in neurodegenerative disorders. Neurobiol Dis. 2014; 72 Pt A: 22.
  4. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63:287–303.
  5. Maulik M, Westaway D, Jhamandas JH, Kar S. Role of cholesterol in APP metabolism and its significance in Alzheimer’s disease pathogenesis. Mol Neurobiol. 2013;47:        37–63.
  6. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774-83.
  7. Reitz C. Dyslipidemia and dementia: Current epidemiology, genetic evidence, and mechanisms behind the associations. J Alzheimers Dis. 2012;2127-45.
  8. Gamba P, Testa G, Sottero B, Gargiulo S, Poli G, Leonarduzzi G. The link between altered cholesterol metabolism and Alzheimer's disease. Ann N Y Acad Sci. 2012;1259:54-64.
  9. Di Paolo G, Kim T W. Linking lipids to Alzheimer's disease: Cholesterol and beyond. Nat Rev Neurosci. 2011;12(5):284-96.
  10. Akram A, Schmeidler J, Katsel P, Hof PR, Haroutunian V. Increased expression of cholesterol transporter ABCA1 is highly correlated with severity of dementia in AD hippocampus. Brain Res. 2010;1318:167−77.
  11. Kim J, Yoon H, Ramirez CM, Lee SM, Hoe HS, Fernandez-Hernando C. MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression. Exp Neurol. 2012;235:476−83.
  12. Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci. 2010;30:14946−54.
  13. Qosa H, Abuznait AH, Hill RA, Kaddoumi A. Enhanced brain Amyloid-beta clearance by Rifampicin and Caffeine as a possible protective mechanism against Alzheimer’s disease. J Alzheimers Dis. 2012;30:1−15.
  14. Tai LM, Loughlin AJ, Male DK, Romero IA. P-glycoprotein and breast cancer resistance protein restrict apical-tobasolateral permeability of human brain endothelium to amyloid-beta. J Cereb Blood Flow Metab. 2009;29:1079−83.
  15. Kim WS, Rahmanto AS, Kamili A, Rye KA, Guillemin GJ, Gelissen IC, et al. Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation. J Biol Chem. 2007;282:2851−61.
  16. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008;58:681–93.
  17. Lin MS, Chen LY, Wang SS, Chang Y, Chen WY. Examining the levels of ganglioside and cholesterol in cell membrane on attenuation the cytotoxicity of beta-amyloid peptide. Colloids Surf B Biointerfaces. 2008;65(2):172–7.
  18. Abramov AY, Ionov M, Pavlov E, Duchen MR. Membrane cholesterol content plays a key role in the neurotoxicity of beta-amyloid: Implications for Alzheimer's disease. Aging Cell. 2011;10(4):595–603.
  19. Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002;277(35):32046–53.
  20. Fan J, Donkin J, Wellington C. Greasing the wheels of Abeta clearance in Alzheimer’s disease: the role of lipids and apolipoprotein E. Biofactors. 2009;35:239−48.
  21. Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: Normal biology and roles in Alzheimer disease. Cold Spring Harbor Perspect Med. 2012;2:a006312. doi: 10.1101/cshperspect.a006312
  22. Koldamova R, Fitz NF, Lefterov I. ATP-binding cassette transporter A1: From metabolism to neurodegeneration. Neurobiol Dis. 2014;72:13–21.
  23. O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci. 2011;34:185–204.
  24. Maulik M, Westaway D, Jhamandas JH, Kar S. Role of cholesterol in APP metabolism and its significance in Alzheimer’s disease pathogenesis. Mol Neurobiol. 2013;47:37–63.
  25. Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y. Reducing human apolipoprotein Levels attenuates age-dependent A beta accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci. 2012;32:4803–11.
  26. Lin TW. Different types of exercise induce differential effects on neuronal adaptations and memory performance. Neurobiol Learn Mem. 2012;97(1):140-7.
  27. Thomas A. The effects of physical activity on brain structure. Front Psychol. 2012;3:86-97.
  28. Cotman CW, Berchtold NC. Exercise: A behavioral intervention to enhance brain health and plasticity. Trends Neurosci.. 2002;25(6):295-301.
  29. Garcia PC. Different protocols of physical exercise produce different effects on synaptic and structural proteins in motor areas of the rat brain. Brain Res. 2012;1456(0):36-48.
  30. Rockwood K, Middleton L. Physical activity and the maintenance of cognitive function. Alzheimers Dement. 2007;3:38-44.
  31. Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, et al. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem. 2005;280: 43243–56.
  32. Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, et al. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem. 2004;279:41197–207.
  33. Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, et al. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem. 2005;280:43236–42.
  34. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidationof astrocyte-secreted apoE. J Biol Chem. 2004;279:40987–93
  35. Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, et al. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008;118:671–82.
  36. Corona AW, Kodoma N, Casali BT, Landreth GE. ABCA1 is necessary for bexarotene-mediated clearance of soluble amyloid beta from the hippocampus of APP/PS1 mice. J Neuroimmune Pharmacol. 2016;11(1):61-72.
  37. Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JA, Holtzman DM, et al. Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis. J Neurosci. 2011;31:7049−59.
  38. Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, et al. ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem. 2010;285:34144–54.
  39. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002; 297:353−6.
  40. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. ApoEdirected therapeutics rapidly clear b-amyloid and reverse deficits in AD mouse models. Science. 2012;335:1503–6.
  41. Zagaar M, Dao A, Levine A, Alhaider I, Alkadhi K. Regular exercise prevents sleep deprivation associated impairment of long-term memory and synaptic plasticity in the CA1 area of the hippocampus. Sleep. 2013;36(5):751-61.
  42. Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, Alkadhi K. The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Dis. 2012;45(3):1153-62.
  43. Zeidabadi R, Arabameri E, Naghdi N, Boloori B. The effect of short- and long-term physical activity with very low intensity on learning and spatial memory in mice. Motor Behavior. 2014;15:155-72. (In Persian).
  44. Sandoval-Hernández AG, Buitrago L, Moreno H, Cardona-Gómez GP, Arboleda G. role of liver X receptor in AD pathophysiology. PLoS One. 2015;10(12):e0145467.
  45. Shweta MC, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-mediated amyloid learance and reversal of cognitive deficitsina murine model of Alzheimer’s disease. J Neurosci. 2012;32(30):10117–28.
  46. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–71.
  47. Seo JB, Moon HM, Kim WS, Lee YS, Jeong HW, Yoo EJ, et al. Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor gamma expression. Mol Cell Biol. 2004;24:3430–44.
  48. Yue L, Mazzone T. Peroxisome proliferator-activated receptor {gamma} stimulation of adipocyte ApoE gene transcription mediated by the liver receptor X pathway. J Biol Chem. 2009;284:10453–61.
  49. Tal AR. Cholesterol efflux pathways and other potential mechanisms involved in theathero-protective effect of highdensity lipoproteins. J Intern Med. 2008; 263:256–73.
  50. Rubic T, Lorenz RL. Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10. Cardiovasc Res. 2006;69(2):527-35.
  51. Han X, Kitamoto S, Lian Q, Boisvert WA. Interleukin-10 facilitates both cholesterol uptake and efflux in macrophages. J Biol Chem. 2009;284(47):32950-8.
  52. Zhuang J, Zhang H, Zhou R, Chen L, Chen J, Shen X. Regulation of prostaglandin F2α against β amyloid clearance and its inflammation induction through LXR/RXR heterodimer antagonism in microglia. Prostaglandins Other Lipid Mediat. 2013;106:     45-52.
  53. Alexis MS, Bronwen M, Stuart M. Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer's disease. Curr Alzheimer Res. 2012;9(1):86–92.
  54. Nichol KE, Poon WW, Parachikova AI, Cribbs DH. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008; 5:13-24.
  55. Ghanbari-Niaki A, Khabazian BM, Hossaini-Kakhak SA, Rahbarizadeh F, Hedayati M. Treadmill exercise enhances ABCA1 expression in rat liver. Biochem Biophys Res Commun. 2007;361(4):841-6.
  56. Ghorbanian B, Ravassi A, Kordi MR, Hedayati M. The effects of rope training on lymphocyte ABCA1 expression, plasma ApoA-I and HDL-c in boy adolescents. Int J Endocrinol Metab. 2013;11(2):76-81.
  57. Khabazian BM, Ghanbari-Niaki A, Safarzadeh-Golpordesari Ar, Ebrahimi M, Rahbarizadeh F, Abednazari H. Endurance training enhances ABCA1 expression in rat small intestine. Eur J Appl Physiol. 2009;107(3):351-8.
  58.  Rashidlamir A , Ghanbari Niaki A,  Saadat-Nia A. The effect of eight weeks of wrestling and wrestling technique-based circuit training on lymphocyte ABCA1 gene expression and plasma apolipoprotein A-I. World J Sport Sci. 2011;4(2):144-50.
  59.  Ghanbari-Niaki A, Ghanbari-Abarghooi S, Rahbarizadeh F, Zare-Kookandeh N, Gholizadeh M, Roudbari F, et al. Heart ABCA1 and PPAR- α genes expression responses in male rats: Effects of high intensity treadmill running training and aqueous extraction of black crataegus-pentaegyna. Res Cardiovasc Med. 2013;2(4):153-9.
  60. Uysal N,  Tugyan K,  Kayatekin BM, Acikgoz O. The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory. Neurosci Lett. 2005;383(3):241-5.
Sport Physiology
Volume 12, Issue 45
Spring 2020
April 2020
Pages 61-78

  • Receive Date 04 January 2018
  • Revise Date 06 May 2018
  • Accept Date 03 June 2018