Document Type : Research Paper I Open Access I Released under (CC BY-NC) license
Authors
1 Department of Sports physıology, centeral Tehran Branch Islamic Azad University, Tehran, Iran
2 Department of sport physiology, faculty of physical education and sport sciences, Islamic Azad University Central Tehran Branch, Tehran, Iran
Abstract
Aim: The aim of the present study was to investigate the effect of 4 weeks of aerobic exercise on cognitive function and mitochondrial dynamics in the hippocampal tissue of male Wistar rats with Alzheimer's disease.
Methods: For this purpose, 21 male Wistar rats at 20 months of age were randomly divided into 3 groups: Alzheimer's disease (n = 7), Alzheimer's disease + aerobic exercise (n = 7) and control group (n = 7). Alzheimer's disease was induced by intrahippocampal injection of Aβ42 (1 microliter per side). Seven days after surgery, the exercise group performed 4 weeks of treadmill training (5 days per week at a speed of 10 to 15 m/min). Forty-eight hours after the last training session, the animals underwent behavioral tests. Twenty-four hours after the behavioral test, all rats were killed and hippocampal tissue was extracted. The mRNA expression of OPA1, Mfn2 and Drp1 genes was assayed using Real Time-PCR. One-way analysis of variance was used for statistical analysis.
Ethical Considerations: All stages of the study were conducted according to the ethical guidelines and authorization of Research Deputy of Islamic Azad University, Central Tehran Branch No. IR.IAU.TMU.REC.1399.124.
Results: The results showed that spatial learning (P ≤ 0.001) and memory performance (P ≤ 0.001) as well as the gene expression of OPA1 (P ≤ 0.001) and Mfn2 (P ≤ 0.001) in animals with Alzheimer's disease decreased compared to the control group, while the gene expression of Drp1 increased (P ≤ 0.001). Aerobic exercise in patient animals improved spatial learning (P ≤ 0.001) and memory performance (P ≤ 0.001), increased hippocampal OPA1 (P ≤ 0.001) and Mfn2 (P ≤ 0.001) genes expression, and decreased Drp1 gene expression compared with Alzheimer's disease group (P ≤ 0.001).
Conclusion: In general, it seems that aerobic exercise can improve spatial learning and memory performance in Alzheimer's disease by modulating abnormal mitochondrial dynamics.
Keywords
- Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S. 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. 2018.
- Azimi SMA GR, Naghdi N, Khodadadi D, Zarezade Mehrizi AA. The effect of the forced treadmill running on genes expression of the PGC-1α, FNDC5 and
BDNF in hippocampus of male rats. Journal of Practical Studies of Biosciences in Sport. 2019;7(14):91-101.
- Bartolome F, de la Cueva M, Pascual C, Antequera D, Fernandez T, Gil C, et al. Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition. Alzheimer's research & therapy. 2018;10(1):1-15.
- Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nature reviews neurology. 2015;11(1):11-24.
- Cha M-Y, Han S-H, Son SM, Hong H-S, Choi Y-J, Byun J, et al. Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death. PloS one. 2012;7(4):e34929.
- Cheng A, Wan R, Yang J-L, Kamimura N, Son TG, Ouyang X, et al. Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nature communications. 2012;3(1):1-12.
- Cho D-H, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, et al. S-nitrosylation of Drp1 mediates β-amyloid-related mitochondrial fission and neuronal injury. Science. 2009;324(5923):102-5.
- Fealy CE, Mulya A, Lai N, Kirwan JP. Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle. Journal of Applied Physiology. 2014;117(3):239-45.
- Gusdon AM, Callio J, Distefano G, O'Doherty RM, Goodpaster BH, Coen PM, et al. Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Experimental gerontology. 2017;90:1-13.
- He X-f, Liu D-x, Zhang Q, Liang F-y, Dai G-y, Zeng J-s, et al. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Frontiers in molecular neuroscience. 2017;10.
- Intlekofer KA, Cotman CW. Exercise counteracts declining hippocampal function in aging and Alzheimer's disease. Neurobiology of disease. 2013;57:47-55.
- Joseph AM, Adhihetty PJ, Leeuwenburgh C. Beneficial effects of exercise on age‐related mitochondrial dysfunction and oxidative stress in skeletal muscle. The Journal of physiology. 2016;594(18):5105-23.
- Khodadadi D, Gharakhanlou R, Naghdi N, Salimi M, Azimi M, Shahed A, et al. Treadmill Exercise Ameliorates Spatial Learning and Memory Deficits Through Improving the Clearance of Peripheral and Central Amyloid-Beta Levels. Neurochemical Research. 2018:1-14.
- Khodadadi D, Gharakhanlou R, Naghdi N, Salimi M, Azimi SM, Shahed A. The effect of 4 weeks of exercise preconditioning on soluble amyloid beta level and memory impairment in rats with Alzheimer's disease induced by Aβ1-42 injection. Razi Journal of Medical Sciences. 2018;24(165):74-84.
- Kou X, Li J, Liu X, Chang J, Zhao Q, Jia S, et al. Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics. Journal of Applied Physiology. 2017;122(6):1462-9.
- Manczak M, Calkins MJ, Reddy PH. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Human molecular genetics. 2011;20(13):2495-509.
- Paxinos G, Watson C. The rat brain in stereotaxic coordinates: San Diego: Academic. 1998.
- Pfaffl MW. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic acids research. 2001;29(9):e45-e.
- Querfurth H, LaFerla F. Alzheimer's disease N Engl J Med. 2010. 2010;329:10.
- Rabinovici GD, Furst AJ, Alkalay A, Racine CA, O’Neil JP, Janabi M, et al. Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden. Brain. 2010;133(2):512-28.
- Schönfeld P, Reiser G. Why does brain metabolism not favor burning of fatty acids to provide energy?-Reflections on disadvantages of the use of free fatty acids as fuel for brain. Journal of Cerebral Blood Flow & Metabolism. 2013;33(10):1493-9.
- Sheikhzadeh F, Etemad A, Khoshghadam S, Asl NA, Zare P. Hippocampal BDNF content in response to short-and long-term exercise. Neurological Sciences. 2015;36(7):1163-6.
- Sita G, Hrelia P, Graziosi A, Morroni F. Back to the fusion: Mitofusin-2 in Alzheimer’s disease. Journal of Clinical Medicine. 2020;9(1):126.
- Tyumentsev MA, Stefanova NA, Muraleva NA, Rumyantseva YV, Kiseleva E, Vavilin VA, et al. Mitochondrial dysfunction as a predictor and driver of Alzheimer’s disease-like pathology in OXYS rats. Journal of Alzheimer's Disease. 2018;63(3):1075-88.
- Vaynman S, Ying Z, Gomez‐Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. European Journal of Neuroscience. 2004;20(10):2580-90.
- Wang X, Su B, Lee H-g, Li X, Perry G, Smith MA, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. Journal of Neuroscience. 2009;29(28):9090-103.
- Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell metabolism. 2013;18(5):649-59.
- Youle RJ, Van Der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337(6098):1062-5.
29. 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. Neurobiology of disease. 2012;45(3):1153-62.
)