The effects of aerobic training before and after the induction of Alzheimer’s disease on ABCA1 and APOE mRNA expression and the level of soluble Aβ1-42 in the hippocampus of male Wistar rats

Document Type : Original Article


1 Faculty of Sport Sciences, Ferdowsi University of Mashhad, Mashhad, Iran

2 Faculty of Humanities, Tarbiat Modares University, Tehran, Iran


Objective(s): The purpose of this study was to investigate the effects of aerobic training before and after the induction of Alzheimer’s disease on ABCA1 and APOE mRNA expression and the level of soluble Aβ1-42 in the hippocampus of male Wistar rats.
Materials and Methods: Ninety six eight-week-old male Wistar rats were randomly divided into two groups: Training (n=48) and Rest (n=48). After four weeks, each group was randomly divided into two subgroups: intra-hippocampal injection of Aβ1-42 (n=24) and DMSO (n=24). Then, each group was again randomly divided into two groups: Training (n=12) and Rest (n=12). After four weeks, each group was again randomly divided into two groups: Behavioral test (n=7) and sacrificed (n=5).
Results: The one-way ANOVA showed a significant increase in the mRNA expression of ABCA1 (P<0.05), a significant decrease in the level of soluble Aβ1-42, and no significant difference in the expression of APOE mRNA (P>0.05) in the hippocampus as a result of training. The analysis of the Morris water maze data showed that intra-hippocampal injection of Aβ1-42 impaired spatial learning and memory and exercise improved spatial learning (P<0.05) and memory (P<0.05).
Conclusion: Therefore, aerobic training by a significant increase in the mRNA expression of ABCA1, which is the main factors of lipid metabolism in the brain and which is involved in the pathology of Alzheimer’s disease, can be consistent with improving cognitive function as an effective way of preventing and improving the symptoms of Alzheimer’s disease.


Main Subjects

1. De Souza LC, Sarazin M, Goetz C, Dubois B. Clinical investigations in primary care. Front Neurol Neurosci. 2009;24:1-11.
2. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239-259.
3. Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci. 2010;30:14946-14954.
4. Wenk GL. Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J Clin Psychiatry. 2006;3:3-7.
5. 2013 Alzheimer’s disease facts and figures. Alzheimers Dement. 2013;9:208-245.
6.     Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;8:741-766.
7.     Hardy J. A hundred years of Alzheimer’s disease research. Neuron. 2006;52:3-13.
8.     Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353-356.
9.     Allinquant B, Clamagirand C, Potier MC. Role of cholesterol metabolism in the pathogenesis of Alzheimer’s disease. Curr Opin Clin Nutr Metab Care. 2014;17:319-323.
10. Reitz C. Dyslipidemia and the risk of Alzheimer’s disease. Curr Atheroscler Rep. 2013;15:307-318.
11. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45:1452-1458.
12. Dorszewska J, Prendecki M, Oczkowska A, Dezor M, Kozubski W. Molecular basis of familial and sporadic Alzheimer’s Disease. Curr Alzheimer Res. 2016;13:952-963.
13. Kim J, Yoon H, Horie T, Burchett JM, Restivo JL, Rotllan N, et al. microRNA-33 regulates apoE lipidation and amyloid-beta metabolism in the brain. J Neurosci. 2015;35:14717-14726.
14. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63:287-303.
15. 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;35:239-248.
16. Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006312.
17. Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43:333-344.
18. Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y. Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci. 2012;32:4803-4811.
19. Stukas S, Robert J, Wellington CL. High-density lipoproteins and cerebrovascular integrity in Alzheimer’s disease. Cell Metab. 2014;19:574-591.
20. Hayden MR, Clee SM, Brooks-Wilson A, Genest J, Attie A, Kastelein JJ. Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency. Curr Opin Lipidol. 2000;11:117-122.
21. Koldamova R, Fitz NF, Lefterov I. ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobio Dis. 2014;72:13-21.
22. O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 2011;34:185-204.
23. 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.
24. Lin TW, Chen SJ, Huang TY, Chang CY, Chuang JI, Wu FS, et al. Different types of exercise induce differential effects on neuronal adaptations and memory performance. Neurobiol Learn Mem. 2012;97:140-147.
25. Thomas AG, Dennis A, Bandettini PA, Johansen-Berg H. The effects of aerobic activity on brain structure. Front Psychol. 2012;3:86-97.
26. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295-301.
27. Garcia PC, Real CC, Ferreira AF, Alouche SR, Britto LR, Pires RS. Different protocols of physical exercise produce different effects on synaptic and structural proteins in motor areas of the rat brain. Brain Res. 2012;1456:36-48.
28.    Rockwood K, Middleton L. Physical activity and the maintenance of cognitive function. Alzheimers Dement. 2007;3:38-44.
29. 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;280:43243-43256.
30. 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;279:41197-41207.
31. Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005;280:43224-43235.
32. 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;280:43236-43242.
33. 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 lipidation of astrocyte-secreted apoE. J Biol Chem. 2004;279:40987-40993.
34. 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;118:671-682.
35. 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;11:61-72.
36. 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 neuroscience. 2011;31:7049-7059.
37. 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;285:34144-34154.
38. Dao AT, Zagaar MA, Alkadhi KA. Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease. Mol Neurobiol. 2015;52:1067-1076.
39. Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, et al. The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Dis. 2012;45:1153-1162.
40. Doost Mohammadpour J, Hosseinmardi N, Janahmadi M, Fathollahi Y, Motamedi F, Rohampour K. Non-selective NSAIDs improve the amyloid-beta-mediated suppression of memory and synaptic plasticity. Pharmacol Biochem Behav. 2015;132:33-41.
41. Paxinos G  WC. The rat brain stereotaxic co-ordinates. Massachusetts. 2007.
42. Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2ˆ(–delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biol Trace Elem Res. 2013;3:71-85.
43. Tahmasebi Boroujeni S, Naghdi N, Shahbazi M, Farrokhi A, Bagherzadeh F, Kazemnejad A, et al. The effect of severe zinc deficiency and zinc supplement on spatial learning and memory. Biol Trace Elem Res. 2009;130:48-61.
44. Sandoval-Hernandez AG, Buitrago L, Moreno H, Cardona-Gomez GP, Arboleda G. Role of liver X receptor in AD pathophysiology. PloS one. 2015;10:e0145467.
45.Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci. 2012;32:10117-10128.
46. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol cell. 2001;7:161-171.
47. 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;284:10453-10461.
48. 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 γ Expression. Mol Cell Biol. 2004;24:3430-3444.
49. Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med. 2008;263:256-273.
50. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008;58:681-693.
51. Lin TW, Shih YH, Chen SJ, Lien CH, Chang CY, Huang TY, et al. Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer’s disease (APP/PS1) transgenic mice. Neurobiol Learn Mem. 2015;118:189-197.
52. Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008;5:13-27.
53. Adlard PA, James SA, Bush AI, Masters CL. Beta-amyloid as a molecular therapeutic target in Alzheimer’s disease. Drugs Today (Barc). 2009;45:293-304.
54. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005;120:701-713.
55. Adlard PA, Perreau VM, Pop V, Cotman CW. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:4217-4221.
56. Uysal N, Tugyan K, Kayatekin BM, Acikgoz O, Bagriyanik HA, Gonenc S, et al. The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory. Neurosci Lett. 2005;383:241-245.
57. Hori Y, Hashimoto T, Nomoto H, Hyman BT, Iwatsubo T. Role of Apolipoprotein E in beta-Amyloidogenesis: Isoform-specific effects on protofibril to fibril conversion of Abeta in vitro and brain Abeta deposition in vivo. J Biol Chem. 2015;290:15163-15174.
58. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci. 1996;19:53-77.
59. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:5644-5651.
60. Roses AD, Saunders AM, Corder EH, Pericak-Vance MA, Han SH, Einstein G, et al. Influence of the susceptibility genes apolipoprotein E-epsilon 4 and apolipoprotein E-epsilon 2 on the rate of disease expressivity of late-onset Alzheimer’s disease. Arzneimittelforschung. 1995;45:413-417.
61. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat genet. 1994;7:180-184.
62. Tokuda T, Calero M, Matsubara E, Vidal R, Kumar A, Permanne B, et al. Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid beta peptides. Biochem J. 2000;348:359-365.