Abstract
This study was designed to investigate the potential neuroprotective effect of exercise in a mouse model of Alzheimer’s disease (AD) induced by intracerebroventricular (i.c.v.) injection of beta-amyloid1–40 (Aβ1–40) peptide. For this aim, male Swiss Albino mice were submitted to swimming training (ST) with progressive increase in intensity and duration for 8 weeks before Aβ1–40 administration (400 pmol/animal; 3 μl/site, i.c.v. route). The cognitive behavioral, oxidative stress, and neuroinflammatory markers in hippocampus and prefrontal cortex of mice were assessed 7 days after Aβ1–40 administration. Our results demonstrated that ST was effective in preventing impairment in short- and long-term memories in the object recognition test. ST attenuated the increased levels of reactive species and decreased non-protein thiol levels in hippocampus and prefrontal cortex induced by Aβ1–40. Also, Aβ1–40 inhibited superoxide dismutase activity and increased glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities in hippocampus and prefrontal cortex—alterations that were mitigated by ST. In addition, ST was effective against the increase of tumor necrosis factor-alpha and interleukin-1 beta levels and the decrease of interleukin-10 levels in hippocampus and prefrontal cortex. This study confirmed the hypothesis that exercise is able to protect against some mechanisms of Aβ1–40-induced neurotoxicity. In conclusion, we suggest that exercise can prevent the cognitive decline, oxidative stress, and neuroinflammation induced by Aβ1–40 in mice supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of AD.
Similar content being viewed by others
References
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126
Aksu I, Topcu A, Camsari UM, Acikgoz O (2009) Effect of acute and chronic exercise on oxidant–antioxidant equilibrium in rat hippocampus, prefrontal cortex and striatum. Neurosci Lett 452:281–285
Almeida WS, Lima LC, Cunha VN, Cunha RR, Araújo RC, Barros CC, Simões HG, Campbell CS (2011) Assessment of aerobic capacity during swimming exercise in ob/ob mice. Cell Biochem Funct 29:666–672
Bagheri M, Joghataei MT, Mohseni S, Roghani M (2011) Genistein ameliorates learning and memory deficits in amyloid β(1–40) rat model of Alzheimer’s disease. J Neuroimmunol 113:49–62
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031
Banerjee AK, Mandal A, Chanda D, Chakraborti S (2003) Oxidant, antioxidant and physical exercise. Mol Cell Biochem 253:307–312
Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804
Bloomer RJ, Goldfarb AH (2004) Anaerobic exercise and oxidative stress: a review. Can J Appl Physiol 29:245–263
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principles of protein-dye binding. Anal Biochem 72:248–254
Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490
Cassina A, Radi R (1996) Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 328:309–316
Cechetti F, Worm PV, Elsner VR, Bertoldi K, Sanches E, Bem J, Siqueira IR, Netto CA (2012) Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the rat. Neurobiol Learn Mem 97:90–96
Contarteze RVL, Manchado FDB, Gobatto CA, De Mello MAR (2008) Stress biomarkers in rats submitted to swimming and treadmill running exercises. Comp Biochem Physiol A Mol Integr Physiol 151:415–422
Davisson RL, Yang G, Beltz TG, Cassell MD, Johnson AK, Sigmund CD (1998) The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes. Circ Res 83:1047–1058
Devi SA, Kiran TR (2004) Regional responses in antioxidant system to exercise training and dietary vitamin E in aging rat brain. Neurobiol Aging 25:501–508
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77
Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. Behav Brain Res 31:47–59
Fischer JC, Ruitenbeek W, Berden JA, Trijbels JM, Veerkamp JH, Stadhouders AM, Sengers RC, Janssen AJ (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36
García-Capdevila S, Portell-Cortés I, Torras-Garcia M, Coll-Andreu M, Costa-Miserachs D (2009) Effects of long-term voluntary exercise on learning and memory processes: dependency of the task and level of exercise. Behav Brain Res 202:162–170
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 Alzheimer Dis 24:421–454
Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS (2011) The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11:607–615
Gobatto CA, De Mello MA, Sibuya CY, De Azevedo JR, Dos Santos LA, Kokubun E (2001) Maximal lactate steady state in rats submitted to swimming exercise. Comp Biochem Physiol A Mol Integr Physiol 130:21–27
Haass C, De Strooper B (1999) The presenilins in Alzheimer’s disease: proteolysis holds the key. Science 286:916–919
Habig WH, Jakoby WB (1981) Glutathione S-transferases (rat and human). Methods Enzymol 77:218–231
Hardy J (2006) Has the amyloid cascade hypothesis for Alzheimer’s disease been proved? Curr Alzheimer Res 3:71–73
Hopkins ME, Bucci DJ (2010) BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memory. Neurobiol Learn Mem 94:278–284
Huang TH, Hsieh SS, Liu SH, Chang FL, Lin SC, Yang RS (2010) Swimming training increases the post-yield energy of bone in young male rats. Calcif Tissue Int 86:142–153
Ji LL, Gomez-Cabrera MC, Vina J (2006) Exercise and hormesis activation of cellular antioxidant signaling pathway. Ann NY Acad Sci 1067:425–435
Jolitha AB, Subramanyam MVV, Asha Devi S (2006) Modification by vitamin E and exercise of oxidative stress in regions of aging rat brain: studies on superoxide dismutase isoenzymes and protein oxidation status. Exp Gerontol 41:753–763
Kramer AF, Erickson KI, Colcombe SJ (2006) Exercise, cognition and aging brain. J Appl Physiol 101:1237–1242
Latini A, Rodriguez M, Borba RR, Scussiato K, Leipnitz G, Reis DA, Da Costa GF, Funchal C, Jacques-Silva MC, Buzin L, Giugliani R, Cassina A, Radi R, Wajner M (2005) 3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience 135:111–120
Lau YS, Patki G, Das-Panja K, Le WD, Ahmad SO (2011) Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. Eur J Neurosci 33:1264–1274
Lautenschlager NT, Cox K, Cyarto EV (2012) The influence of exercise on brain aging and dementia. Biochim Biophys Acta 1822:474–481
Leek BT, Mudaliar SR, Henry R, Mathieu-Costello O, Richardson RS (2001) Effect of acute exercise on citrate synthase activity in untrained and trained human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 280:441–447
Leem YH, Lee YL, Son HJ, Lee SH (2011) Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochem Biophys Res Commun 406:359–365
Liu HL, Zhao G, Cai K, Zhao HH, Shi LD (2011) Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation. Behav Brain Res 218:308–314
Loetchutinat C, Kothan S, Dechsupa S, Meesungnoen J, Jay-Gerin J, Mankhetkorn S (2005) Spectrofluorometric determination of intracellular levels of reactive oxygen species in drug-sensitive and drug-resistant cancer cells using the 2′,7′-dichlorofluorescein diacetate assay. Radiat Phys Chem 72:323–331
Love LK, LeBlanc PJ, Inglis JG, Bradley NS, Choptiany J, Heigenhauser GJ, Peters SJ (2011) The relationship between human skeletal muscle pyruvate dehydrogenase phosphatase activity and muscle aerobic capacity. J Appl Physiol 111:427–434
Mann PB, Jiang W, Zhu Z, Wolfe P, McTiernan A, Thompson HJ (2010) Wheel running, skeletal muscle aerobic capacity and 1-methyl-1-nitrosourea induced mammary carcinogenesis in the rat. Carcinogenesis 31:1279–1283
Medeiros R, Figueiredo CP, Pandolfo P, Duarte FS, Prediger RDS, Passos GF, Calixto JB (2010) The role of TNF-α signaling pathway on COX-2 upregulation and cognitive decline induced by β-amyloid peptide. Behav Brain Res 209:165–173
Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and simple assay for superoxide dismutase. J Biol Chem 247:3170–3175
Mota BC, Pereira L, Souza MA, Silva LFA, Magni DV, Ferreira APO, Oliveira MS, Furian AF, Mazzardo-Martins L, Da Silva MD, Santos ARS, Ferreira J, Fighera MR, Royes LFF (2010) Exercise pre-conditioning reduces brain inflammation and protects against toxicity induced by traumatic brain injury: behavioral and neurochemical approach. Neurotox Res 21:175–184
Murgas P, Godoy B, von Bernhardi R (2012) Aβ potentiates inflammatory activation of glial cells induced by scavenger receptor ligands and inflammatory mediators in culture. Neurotox Res 22:69–78
Nunomura A, Castellani RJ, Xiongwei Z, Moreira PI, Perry G, Smith MA (2006) Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 65:631–641
Oyatsi F, Whiteley CG (2012) Interaction of superoxide dismutase with the glycine zipper regions of β-amyloid peptides: is there an implication towards Alzheimer’s disease and oxidative stress? J Enzyme Inhib Med Chem. doi:10.3109/14756366.2012.680063
Palop JJ, Mucke L (2010) Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818
Pang TYC, Hannan AJ (2012) Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity. Neuropharmacology 64:515–528
Parachikova A, Nichol KE, Cotman CW (2008) Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 30:121–129
Passos GF, Figueiredo CP, Prediger RDS, Silva KABS, Siqueira JM, Duarte FS, Leal PC, Medeiros R, Calixto JB (2010) Involvement of phosphoinositide 3-kinase gamma in the neuro-inflammatory response and cognitive impairments induced by beta-amyloid 1–40 peptide in mice. Brain Behav Immun 24:493–501
Piermartiri TCB, Figueiredo CP, Rial D, Duarte FS, Bezerra SC, Mancini G, De Bem AF, Prediger RDS, Tasca CI (2010) Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β1–40 administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol 226:274–284
Prediger RDS, Franco JL, Pandolfo P, Medeiros R, Duarte FS, Di Giunta G, Figueiredo CP, Farina M, Calixto JB, Takahashi RN, Dafre AL (2007) Differential susceptibility following β-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 177:205–213
Radak Z, Taylor AW, Ohno H, Goto S (2001) Adaptation to exercise-induced oxidative stress: from muscle to brain. Exerc Immunol Rev 7:90–107
Radak Z, Chung HY, Goto S (2008) Systemic adaptation to oxidative challenge induced by regular exercise. Free Radic Biol Med 44:153–159
Richter H, Ambrée O, Lewejohann L, Herring A, Keyvani K, Paulus W, Palme R, Touma C, Schäbitz WR, Sachser N (2008) Wheel-running in a transgenic mouse model of Alzheimer’s disease: protection or symptom? Behav Brain Res 190:74–84
Santos DB, Peres KC, Ribeiro RP, Colle D, dos Santos AA, Moreira EL, Souza DO, Figueiredo CP, Farina M (2012) Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid β peptide in mice. Exp Neurol 233:767–775
Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212
Souza MA, Oliveira MS, Furian AFF, Rambo LM, Ribeiro LR, Lima FD, Corte LCD, Silva LFA, Retamoso LT, Corte CLD, Puntel GO, Avila DS, Soares FAA, Fighera MR, Mello CF, Royes LFFR (2009) Swimming training prevents pentylenetetrazol-induced inhibition of Na+, K+-ATPase activity, seizures, and oxidative stress. Epilepsia 50:811–823
Squier TC (2001) Oxidative stress and protein aggregation during biological aging. Exp Neurol 36:1539–1550
Stranaham AM, Martin B, Maudsley S (2012) Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer’s disease. Curr Alzheimer Res 9:86–92
Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW (2001) Interleukin-10 in the brain. Crit Rev Immunol 21:427–449
Szczepanik AM, Funes S, Petko W, Ringheim GE (2001) IL-4, IL-10 and IL-13 modulate A beta (1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 113:49–62
Takeda S, Sato N, Niisato K, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Kano M, Morishita R (2009) Validation of Abeta1–40 administration into mouse cerebroventricles as an animal model for Alzheimer disease. Brain Res 1280:137–147
Tarawneh R, Holtzman DM (2010) Biomarkers in translational research of Alzheimer’s disease. Neuropharmacology 59:310–322
Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 37:289–305
Um HS, Kang EB, Koo JH, Kim HT, Lee J, Kim EJ, Yang CH, An GY, Cho IH, Cho JY (2011) Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer’s disease. Neurosci Res 69:161–173
Verri M, Pastoris O, Dossena M, Aquilani R, Guerriero F, Cuzzoni G, Venturini L, Ricevuti G, Bongiorno AI (2012) Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer’s disease. Int J Immunopathol Pharmacol 25:345–353
Vidoni ED, Honea RA, Billinger SA, Swerdlow RH, Burns JM (2011) Cardiorespiratory fitness is associated with atrophy in Alzheimer’s and aging over 2 years. Neurobiol Aging 33:1624–1632
Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 415:482–504
Wendel A (1981) Glutathione peroxidase. Methods Enzymol 177:325–333
Wharton D, Tzagoloff A (1967) Cytochrome oxidase from beef heart mitochondria. Methods Enzymol 10:245–250
Wibom R, Hultman E, Johansson M, Matherei K, Constantin-Teodosiu D, Schantz PG (1992) Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining. J Appl Physiol 73:2004–2010
Winters BD, Saksida LM, Bussey TJ (2008) Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci Biobehav Rev 32:1055–1070
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 35:426–432
Zhao J, O’Connor T, Vassar R (2011) The contribution of activated astrocytes to Aβ production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation 8:150
Acknowledgments
LCS, CBF, LDF, MGG, and ATRG are recipients of CAPES, FAPERGS, CNPq, and PBDA/UNIPAMPA fellowships, respectively.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Souza, L.C., Filho, C.B., Goes, A.T.R. et al. Neuroprotective Effect of Physical Exercise in a Mouse Model of Alzheimer’s Disease Induced by β-Amyloid1–40 Peptide. Neurotox Res 24, 148–163 (2013). https://doi.org/10.1007/s12640-012-9373-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-012-9373-0