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Changes in Aβ42, Neprilysin, and γ-Secretase in the Hippocampus of Male Rats Alzheimer’s model: The Effects of Aerobic Training and Omega-3 Intake

Document Type : Original Article

Author

Department of Physical Education and Sport Science, Bojnourd Branch, Islamic Azad University, Bojnourd, Iran

Abstract

Background: Alzheimer›s disease (AD) is characterized by excessive deposition of the amyloid-β peptide (Aβ) in the central nervous system and reducing its level is the goal of many medications. This study aimed to investigate the effect of aerobic training and omega-3 intake on Aβ42, neprilysin, and γ-secretase levels in the hippocampus of male rats Alzheimer›s model. Methods: Fifty male Wistar rats (age: 12 weeks-old and weight: 222.31±11.91 g), were divided into the five groups including control Alzheimer’s (AC), Alzheimer’s with omega-3 intake (AO), Alzheimer’s training (AT), Alzheimer’s with omega-3 intake and training (AOT) and Healthy Control (HC). AD was induced by the injection of homocysteine (60mM) into the rat brain ventricle. Training on the treadmill with a speed of 20 m/min (60 minutes and 5 days/week) was applied. The supplement group received omega-3 supplement 800 mg/kg of body weight, daily for eight weeks. Levels of Aβ42, γ-secretase, and neprilysin protein were measured using ELISA method. In data analysis, one-way ANOVA and Tukey test as post hoc were used (P < 0.05). Results: The obtained results showed that the level of Aβ42 in the hippocampus of AC group was significantly higher than that of the HC group (P = 0.001). Also, the level of Aβ42 in the hippocampus of AC group was significantly higher as compared to AO, AT, and AOT groups (P values 0.001, 0.007, and 0.003 respectively). The γ-Secretase level in the hippocampus of AC group was significantly higher than that in the HC group (P = 0.001). Moreover, the γ-secretase levels in the hippocampus of the AC group were significantly higher compared to AO, AT, and AOT groups (P values: 0.002, 0.001, and 0.001 respectively). There was no significant difference in neprilysin levels of the hippocampus among the research groups (P = 0.534).
Conclusion: It appears that exercise training and omega-3 consumption, can affect amyloidogenic pathways through reducing the level of γ-secretase, and lead to reduced level of hippocampus Aβ in AD subjects. Therefore, aerobic exercise training and omega-3 intake can be studied as a complementary therapy in Alzheimer’s patients.

Highlights

Ali Yaghoubi(Google scholar)(Pubmed)

Keywords

References

  1. Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014;14:643. doi: 10.1186/1471-2458-14-643.

  2. Morris MS. The role of B vitamins in preventing and treating cognitive impairment and decline. Adv Nutr. 2012;3(6):801- 12. doi: 10.3945/an.112.002535.

  3. Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244. doi: 10.1371/journal.pone.0012244.

  4. Farina N, Jernerén F, Turner C, Hart K, Tabet N. Homocysteine concentrations in the cognitive progression of Alzheimer’s disease. Exp Gerontol. 2017;99:146-50. doi: 10.1016/j. exger.2017.10.008.

  5. Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, et al. Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Neurobiol Dis. 2006;22(3):651-6. doi: 10.1016/j. nbd.2006.01.005.

  6. Cascalheira JF, João SS, Pinhanços SS, Castro R, Palmeira M, Almeida S, et al. Serum homocysteine: interplay with other circulating and genetic factors in association to Alzheimer’s type dementia. Clin Biochem. 2009;42(9):783-90. doi: 10.1016/j.clinbiochem.2009.02.006.

  7. Sharma P, Srivastava P, Seth A, Tripathi PN, Banerjee AG, Shrivastava SK. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog Neurobiol. 2019;174:53-89. doi: 10.1016/j.pneurobio.2018.12.006.

  8. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595-608. doi: 10.15252/emmm.201606210.

  9. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795- 804. doi: 10.1056/NEJMoa1202753.

  10. Selkoe DJ. Alzheimer’s disease--genotypes, phenotype, and treatments. Science. 1997;275(5300):630-1. doi: 10.1126/ science.275.5300.630.

  1. Gispen WH, Biessels GJ. Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci. 2000;23(11):542-9. doi: 10.1016/s0166-2236(00)01656-8.

  2. Fraser ON, Bugnyar T. Ravens reconcile after aggressive conflicts with valuable partners. PLoS One. 2011;6(3):e18118. doi: 10.1371/journal.pone.0018118.

  3. Pearson HA, Peers C. Physiological roles for amyloid beta peptides. J Physiol. 2006;575(Pt 1):5-10. doi: 10.1113/ jphysiol.2006.111203.

  4. Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, et al. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature. 1993;361(6409):260-3. doi: 10.1038/361260a0.

  5. Wilson CA, Doms RW, Lee VM. Intracellular APP processing and A beta production in Alzheimer disease. J Neuropathol Exp Neurol. 1999;58(8):787-94. doi: 10.1097/00005072- 199908000-00001.

  6. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101-12. doi: 10.1038/nrm2101.

  7. Podolski IY, Podlubnaya ZA, Kosenko EA, Mugantseva EA, Makarova EG, Marsagishvili LG, et al. Effects of hydrated forms of C60 fullerene on amyloid 1-peptide fibrillization in vitro and performance of the cognitive task. J Nanosci Nanotechnol. 2007;7(4-5):1479-85. doi: 10.1166/jnn.2007.330.

  8. Yamada K, Nabeshima T. Animal models of Alzheimer’s disease and evaluation of anti-dementia drugs. Pharmacol Ther. 2000;88(2):93-113. doi: 10.1016/s0163- 7258(00)00081-4.

  9. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31-9. doi: 10.1038/361031a0.

  10. Grimm MO, Mett J, Stahlmann CP, Haupenthal VJ, Zimmer VC, Hartmann T. Neprilysin and Aβ clearance: impact of the APP intracellular domain in NEP regulation and implications in Alzheimer’s disease. Front Aging Neurosci. 2013;5:98. doi: 10.3389/fnagi.2013.00098.

  11. Barros AS, Crispim RYG, Cavalcanti JU, Souza RB, Lemos JC, Cristino Filho G, et al. Impact of the chronic omega-3 fatty acids supplementation in hemiparkinsonism model induced by 6-hydroxydopamine in rats. Basic Clin Pharmacol Toxicol. 2017;120(6):523-31. doi: 10.1111/bcpt.12713.

  12. Layé S, Nadjar A, Joffre C, Bazinet RP. Anti-inflammatory effects of omega-3 fatty acids in the brain: physiological mechanisms and relevance to pharmacology. Pharmacol Rev. 2018;70(1):12-38. doi: 10.1124/pr.117.014092.

  13. Echeverría F, Valenzuela R, Catalina Hernandez-Rodas M, Valenzuela A. Docosahexaenoic acid (DHA), a fundamental fatty acid for the brain: new dietary sources. Prostaglandins Leukot Essent Fatty Acids. 2017;124:1-10. doi: 10.1016/j. plefa.2017.08.001.

  14. Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014;15(12):771-85. doi: 10.1038/nrn3820.

  15. Clifford JJ, Drago J, Natoli AL, Wong JY, Kinsella A, Waddington JL, et al. Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience. 2002;109(1):81-8. doi: 10.1016/s0306-4522(01)00409-2.

  16. Grimm MOW, Michaelson DM, Hartmann T. Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer’s disease: a rationale for multi-nutrient dementia prevention. J Lipid Res. 2017;58(11):2083-101. doi: 10.1194/jlr.R076331.

27. Olivera-Perez HM, Lam L, Dang J, Jiang W, Rodriguez F, Rigali E, et al. Omega-3 fatty acids increase the unfolded protein response and improve amyloid-β phagocytosis by macrophages of patients with mild cognitive impairment. FASEB J. 2017;31(10):4359-69. doi: 10.1096/fj.201700290R. 28. Lindsay J, Laurin D, Verreault R, Hébert R, Helliwell B, Hill GB, et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am

J Epidemiol. 2002;156(5):445-53. doi: 10.1093/aje/kwf074. 29. Richards M, Hardy R, Wadsworth ME. Does active leisure protect cognition? Evidence from a national birth cohort. Soc Sci Med. 2003;56(4):785-92. doi: 10.1016/s0277-

9536(02)00075-8.
30. Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane

P, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144(2):73-81. doi: 10.7326/0003-4819- 144-2-200601170-00004.

31. Geda YE, Roberts RO, Knopman DS, Christianson TJ, Pankratz VS, Ivnik RJ, et al. Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch Neurol. 2010;67(1):80-6. doi: 10.1001/archneurol.2009.297.

32. Gómez-Pinilla F, Feng C. Molecular mechanisms for the ability of exercise supporting cognitive abilities and counteracting neurological disorders. In: Boecker H, Hillman CH, Scheef L, Strüder HK, eds. Functional Neuroimaging in Exercise and Sport Sciences. New York, NY: Springer; 2012. p. 25-43. doi: 10.1007/978-1-4614-3293-7_2.

33. Leckie RL, Manuck SB, Bhattacharjee N, Muldoon MF, Flory JM, Erickson KI. Omega-3 fatty acids moderate effects of physical activity on cognitive function. Neuropsychologia. 2014;59:103-11. doi: 10.1016/j. neuropsychologia.2014.04.018.

34. Köbe T, Witte AV, Schnelle A, Lesemann A, Fabian S, Tesky VA, et al. Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment. Neuroimage. 2016;131:226- 38. doi: 10.1016/j.neuroimage.2015.09.050.

35. Chytrova G, Ying Z, Gomez-Pinilla F. Exercise contributes to the effects of DHA dietary supplementation by acting on membrane-related synaptic systems. Brain Res. 2010;1341:32- 40. doi: 10.1016/j.brainres.2009.05.018.

36. Hosseinzadeh S, Dabidi Roshan V, Pourasghar M. Effects of intermittent aerobic training on passive avoidance test (shuttle box) and stress markers in the dorsal hippocampus of Wistar rats exposed to administration of homocysteine. Iran J Psychiatry Behav Sci. 2013;7(1):37-44.

37. Talebi Garekani E, Mohebbi H, Kraemer RR, Fathi R. Exercise training intensity/volume affects plasma and tissue adiponectin concentrations in the male rat. Peptides. 2011;32(5):1008-12. doi: 10.1016/j.peptides.2011.01.027.

38. Fathei M, Nastaran M. The effect of eight weeks aerobic exercise on thyroid hormones in female rats with polycystic ovary syndrome. Int J Sport Stud. 2014;4(3):355-60.

39. Gama CS, Canever L, Panizzutti B, Gubert C, Stertz L, Massuda R, et al. Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: a study in adolescent rats with ketamine-induced model of schizophrenia. Schizophr Res. 2012;141(2-3):162-7. doi: 10.1016/j.schres.2012.08.002.

40. Ma H, Wang J, Wang J, Li Y, Li J. Fish oil ameliorates the

The Effects of aerobic training and omega-3 intake on Aβ42, neprilysin, and γ-Secretase allograft arteriosclerosis of intestine on rats. Pediatr Transplant. 2007;11(2):173-9. doi: 10.1111/j.1399-3046.2006.00636.x.

  1. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006;580(13):2994-3005.

    doi: 10.1016/j.febslet.2006.04.088.

  2. Kamat PK, Vacek JC, Kalani A, Tyagi N. Homocysteine

    induced cerebrovascular dysfunction: a link to Alzheimer’s disease etiology. Open Neurol J. 2015;9:9-14. doi: 10.2174/1874205x01509010009.

  3. Pi T, Liu B, Shi J. Abnormal homocysteine metabolism: an insight of Alzheimer’s disease from DNA methylation. Behav Neurol. 2020;2020:8438602. doi: 10.1155/2020/8438602.

  4. Tawfik A, Mohamed R, Kira D, Alhusban S, Al-Shabrawey M. N-methyl-D-aspartate receptor activation, novel mechanism of homocysteine-induced blood-retinal barrier dysfunction. J Mol Med (Berl). 2021;99(1):119-30. doi: 10.1007/s00109- 020-02000-y.

  5. Oikonomidi A, Lewczuk P, Kornhuber J, Smulders Y, Linnebank M, Semmler A, et al. Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta. J Neurochem. 2016;139(2):324-32. doi: 10.1111/jnc.13766.

  6. Lin HC, Hsieh HM, Chen YH, Hu ML. S-adenosylhomocysteine increases beta-amyloid formation in BV-2 microglial cells by increased expressions of beta-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters. Neurotoxicology. 2009;30(4):622-7. doi: 10.1016/j. neuro.2009.03.011.

  7. Zhang CE, Wei W, Liu YH, Peng JH, Tian Q, Liu GP, et al. Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol. 2009;174(4):1481-91. doi: 10.2353/ajpath.2009.081036.

  8. Li JG, Chu J, Barrero C, Merali S, Praticò D. Homocysteine exacerbates β-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol. 2014;75(6):851-63. doi: 10.1002/ana.24145.

  9. Uslu S, Akarkarasu ZE, Ozbabalik D, Ozkan S, Colak O, Demirkan ES, et al. Levels of amyloid beta-42, interleukin-6 and tumor necrosis factor-alpha in Alzheimer’s disease and vascular dementia. Neurochem Res. 2012;37(7):1554-9. doi: 10.1007/s11064-012-0750-0.

  10. Souza LC, Filho CB, Goes AT, Del Fabbro L, de Gomes MG, Savegnago L, et al. Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by β-amyloid1−40 peptide. Neurotox Res. 2013;24(2):148-63. doi: 10.1007/s12640-012-9373-0.

  11. Capetillo-Zarate E, Gracia L, Tampellini D, Gouras GK. Intraneuronal Aβ accumulation, amyloid plaques, and synapse pathology in Alzheimer’s disease. Neurodegener Dis. 2012;10(1-4):56-9. doi: 10.1159/000334762.

  12. Cavallucci V, D’Amelio M, Cecconi F. Aβ toxicity in Alzheimer’s disease. Mol Neurobiol. 2012;45(2):366-78. doi: 10.1007/s12035-012-8251-3.

  13. Boyd-Kimball D, Mohmmad Abdul H, Reed T, Sultana R, Butterfield DA. Role of phenylalanine 20 in Alzheimer’s amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity. Chem Res Toxicol. 2004;17(12):1743-9. doi: 10.1021/tx049796w.

  14. Nishida Y, Ito S, Ohtsuki S, Yamamoto N, Takahashi T, Iwata N, et al. Depletion of vitamin E increases amyloid beta

accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease. J Biol Chem. 2009;284(48):33400-8. doi: 10.1074/jbc.M109.054056.

55. Prediger RD, Franco JL, Pandolfo P, Medeiros R, Duarte FS, Di Giunta G, et al. Differential susceptibility following beta- amyloid peptide-(1-40) administration in C57BL/6 and Swiss albino mice: evidence for a dissociation between cognitive deficits and the glutathione system response. Behav Brain Res. 2007;177(2):205-13. doi: 10.1016/j.bbr.2006.11.032.

56. Lee CY, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna). 2010;117(8):949-60. doi: 10.1007/s00702-010-0433-4.

57. Agostinho P, Cunha RA, Oliveira C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des. 2010;16(25):2766-78. doi:10.2174/138161210793176572.

58. Rogers JT, Lahiri DK. Metal and inflammatory targets for Alzheimer’s disease. Curr Drug Targets. 2004;5(6):535-51. doi: 10.2174/1389450043345272.

59. Paillard T, Rolland Y, de Souto Barreto P. Protective effects of physical exercise in Alzheimer’s disease and Parkinson’s disease: a narrative review. J Clin Neurol. 2015;11(3):212-9. doi: 10.3988/jcn.2015.11.3.212.

60. Nalivaeva NN, Belyaev ND, Zhuravin IA, Turner AJ. The Alzheimer’s amyloid-degrading peptidase, neprilysin: can we control it? Int J Alzheimers Dis. 2012;2012:383796. doi: 10.1155/2012/383796.

61. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, et al. Metabolic regulation of brain Abeta by neprilysin. Science. 2001;292(5521):1550-2. doi: 10.1126/science.1059946.

62. Kang EB, Cho JY. Effects of treadmill exercise on brain insulin signaling and β-amyloid in intracerebroventricular streptozotocin induced-memory impairment in rats. J Exerc Nutrition Biochem. 2014;18(1):89-96. doi: 10.5717/ jenb.2014.18.1.89.

63. Liu HL, Zhao G, Zhang H, Shi LD. Long-term treadmill exercise inhibits the progression of Alzheimer’s disease-like neuropathology in the hippocampus of APP/PS1 transgenic mice. Behav Brain Res. 2013;256:261-72. doi: 10.1016/j. bbr.2013.08.008.

64. Kang EB, Kwon IS, Koo JH, Kim EJ, Kim CH, Lee J, et al. Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis. 2013;18(11):1332-47. doi: 10.1007/s10495-013- 0884-9.

65. Um HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/ APPsw-transgenic model. Int J Mol Med. 2008;22(4):529-39.

66. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6):295-301. doi: 10.1016/s0166-2236(02)02143-4.

67. 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(17):4217-21. doi: 10.1523/jneurosci.0496-05.2005.

68. Lu B, Chow A. Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res. 1999;58(1):76-87. 69. Trejo JL, Carro E, Torres-Aleman I. Circulating insulin- like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci. 2001;21(5):1628-34. doi: 10.1523/

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144 Journal of Kerman University of Medical Sciences. Volume 30, Number 3, 2023

The Effects of aerobic training and omega-3 intake on Aβ42, neprilysin, and γ-Secretase jneurosci.21-05-01628.2001.

  1. Nichol KE, Parachikova AI, Cotman CW. Three weeks of

    running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behav Brain Res. 2007;184(2):124- 32. doi: 10.1016/j.bbr.2007.06.027.

  2. Cho JY, Um HS, Kang EB, Cho IH, Kim CH, Cho JS, et al. The combination of exercise training and alpha-lipoic acid treatment has therapeutic effects on the pathogenic phenotypes of Alzheimer’s disease in NSE/APPsw-transgenic mice. Int J Mol Med. 2010;25(3):337-46. doi: 10.3892/ ijmm_00000350.

  3. Park KM, Bowers WJ. Tumor necrosis factor-alpha mediated

signaling in neuronal homeostasis and dysfunction. Cell Signal.

2010;22(7):977-83. doi: 10.1016/j.cellsig.2010.01.010.
73. 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. doi: 10.1186/1742-2094-5-13. 74. Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H. Epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation. Neuroreport. 2008;19(13):1329-33. doi: 10.1097/

WNR.0b013e32830b8ae1.

Journal of Kerman University of Medical Sciences
Volume 30, Issue 3
May and June 2023
Pages 136-145
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