Combining aerobic training and resveratrol can improve hippocampal UPRmt genes expression better than either alone in Alzheimer's rats
Subject Areas : Exercise Physiology and Performance
Elham Heydarzadeh
1
,
Kamal Azizbeigi
2
*
,
Khalid Mohamadzadeh Salamat
3
1 - Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran.
2 - Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran.
3 - Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran.
Keywords: Alzheimer's Disease, Exercise, Resveratrol, Mitochondrial Unfolded Protein Response ,
Abstract :
Background: Mitochondrial dysfunction are a key mechanism in the pathogenesis of Alzheimer's disease (AD). Both exercise and resveratrol (RSV) consumption have been identified as potential interventions against AD. The aim of this study was to evaluate the effects of aerobic exercise and RSV on hippocampal UPRmt in rats with AD.
Materials and Methods: In this experimental study, 35 male Wistar rats were divided into five groups: Normal (NO), Alzheimer's (AD), Alzheimer's-Training (ADT), Alzheimer's-Resveratrol (ADRSV), and Alzheimer's-Training-Resveratrol (ADTRSV). The supplement groups received 20 mg of RSV per kg of body weight orally during the intervention period. The aerobic exercise program involved running on a treadmill at speeds ranging from 6 to 18 meters per minute, performed 5 days a week for eight weeks.
Results: AD induction significantly decreased the expression of HSP10, HSP60, and HSP70 (p=0.0001). The expression of HSP60 and HSP70 was significantly increased in the ADT (p=0.024, p=0.041), ADRSV (p=0.029, p=0.046), and ADTRSV (p=0.0001, p=0.0001) groups compared to the AD group. Additionally, ADTRSV showed a greater increase in HSP60 and HSP70 expression compared to ADT (p=0.038, p=0.045) and ADRSV (p=0.032, p=0.040). A significant increase in HSP10 expression was observed in the ADT (p=0.032) and ADTRSV (p=0.0001) groups compared to the AD group, with ADTRSV showing higher levels of HSP10 expression compared to ADRSV (p=0.049).
Conclusion: Aerobic exercise and RSV can reduce neurodegeneration in AD rats by enhancing hippocampal UPRmt gene expression. The combination of exercise and RSV had a greater effect on UPRmt than either intervention alone.
1. Salvatore C, Cerasa A, Castiglioni I. MRI characterizes the progressive course of AD and predicts conversion to Alzheimer’s dementia 24 months before probable diagnosis. Front Aging Neurosci. 2018;10:135. doi: 10.3389/fnagi.2018.00135.
2. Jahn H. Memory loss in Alzheimer's disease. Dialogues Clin Neurosci. 2013;15(4):445-54. doi: 10.31887/DCNS.2013.15.4/hjahn.
3. 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.
4. Chen JX, Yan SS. Role of mitochondrial amyloid-β in Alzheimer's disease. J Alzheimers Dis. 2010;20(s2):S569-S78. doi: 10.3233/JAD-2010-091017.
5. Ruan L, Wang Y, Zhang X, Tomaszewski A, McNamara JT, Li R. Mitochondria-associated proteostasis. Annu Rev Biophys. 2020;49:41-67. doi: 10.1146/annurev-biophys-121219-081235.
6. Quirós PM, Prado MA, Zamboni N, D’Amico D, Williams RW, Finley D, et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol. 2017;216(7):2027-45. doi: 10.1083/jcb.201611039.
7. Deng P, Haynes CM, editors. Mitochondrial dysfunction in cancer: potential roles of ATF5 and the mitochondrial UPR. Semin Cancer Biol. 2017;Elsevier. doi: 10.1016/j.semcancer.2017.04.002.
8. Münch C. The different axes of the mammalian mitochondrial unfolded protein response. BMC Biol. 2018;16(1):81. doi: 10.1186/s12915-018-0523-2.
9. Rath E, Moschetta A, Haller D. Mitochondrial function—gatekeeper of intestinal epithelial cell homeostasis. Nat Rev Gastroenterol Hepatol. 2018;15(8):497-516. doi: 10.1038/s41575-018-0020-4.
10. Cai Y, Arikkath J, Yang L, Guo M-L, Periyasamy P, Buch S. Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. Autophagy. 2016;12(2):225-44. doi: 10.1080/15548627.2015.1112040.
11. Cui K, Li C, Fang G. Aerobic Exercise Delays Alzheimer’s Disease by Regulating Mitochondrial Proteostasis in the Cerebral Cortex and Hippocampus. Life. 2023;13(5):1204. doi: 10.3390/life13051204.
12. Deng L, Zhang Y, Fu Y. Aerobic exercise inhibits neuroinflammation and alleviates cognitive impairment in Alzheimer’s disease model mice. Chin J Tissue Eng Res. 2024;28(14):2209. doi: 10.3969/j.issn.1673-8225.2024.14.008.
13. Grinan-Ferre C, Bellver-Sanchis A, Izquierdo V, Corpas R, Roig-Soriano J, Chillón M, et al. The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer’s disease pathology: From antioxidant to epigenetic therapy. Ageing Res Rev. 2021;67:101271. doi: 10.1016/j.arr.2021.101271.
14. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5(6):493-506. doi: 10.1038/nrd2060.
15. Malhotra A, Bath S, Elbarbry F. An organ system approach to explore the antioxidative, anti-inflammatory, and cytoprotective actions of resveratrol. Oxid Med Cell Longev. 2015;2015:1-9. doi: 10.1155/2015/101324.
16. Ahmed T, Javed S, Javed S, Tariq A, Šamec D, Tejada S, et al. Resveratrol and Alzheimer’s disease: mechanistic insights. Mol Neurobiol. 2017;54:2622-35. doi: 10.1007/s12035-016-9799-7.
17. Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflammation. 2017;14:1-10. doi: 10.1186/s12974-017-1000-1.
18. Corpas R, Griñán-Ferré C, Rodríguez-Farré E, Pallàs M, Sanfeliu C. Resveratrol induces brain resilience against Alzheimer neurodegeneration through proteostasis enhancement. Mol Neurobiol. 2019;56:1502-16. doi: 10.1007/s12035-018-1156-2.
19. Eslimiesfahani D, Oryan S, Khosravi M, Valizadegan F. Effect of fennel extract on the improvement of memory disorders in beta amyloid Alzheimer model of male Wistar rats. 2019.
20. Seyedhosseini Tamijani SM, Beirami E, Ahmadiani A, Dargahi L. Effect of three different regimens of repeated methamphetamine on rats’ cognitive performance. Cogn Process. 2018;19:107-15. doi: 10.1007/s10339-018-0876-x.
21. Wu C, Yang L, Li Y, Dong Y, Yang B, Tucker LD, et al. Effects of exercise training on anxious–depressive-like behavior in Alzheimer rat. Med Sci Sports Exerc. 2020;52(7):1456. doi: 10.1249/MSS.0000000000002244.
22. Monserrat Hernández‐Hernández E, Serrano‐García C, Antonio Vázquez‐Roque R, Díaz A, Monroy E, Rodríguez‐Moreno A, et al. Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats. Synapse. 2016;70(5):206-17. doi: 10.1002/syn.21946.
23. Zhao H, Li N, Wang Q, Cheng X, Li X, Liu T. Resveratrol decreases the insoluble Aβ1–42 level in hippocampus and protects the integrity of the blood–brain barrier in AD rats. Neuroscience. 2015;310:641-9. doi: 10.1016/j.neuroscience.2015.09.027.
24. Marino Gammazza A, Restivo V, Baschi R, Caruso Bavisotto C, Cefalù AB, Accardi G, et al. Circulating molecular chaperones in subjects with amnestic mild cognitive impairment and Alzheimer’s disease: data from the Zabút Aging Project. J Alzheimers Dis. 2022;87(1):161-72. doi: 10.3233/JAD-2019-191013.
25. Macario AJ, de Macario EC. Sick chaperones, cellular stress, and disease. N Engl J Med. 2005;353(14):1489-501. doi: 10.1056/NEJMra044431.
26. Marino Gammazza A, Caruso Bavisotto C, Barone R, Macario ECd, JL Macario A. Alzheimer’s disease and molecular chaperones: current knowledge and the future of chaperonotherapy. Curr Pharm Des. 2016;22(26):4040-9. doi: 10.2174/1381612822666160328122454.
27. Mangione MR, Vilasi S, Marino C, Librizzi F, Canale C, Spigolon D, et al. Hsp60, amateur chaperone in amyloid-beta fibrillogenesis. Biochim Biophys Acta (BBA)-Gen Subj. 2016;1860(11):2474-83. doi: 10.1016/j.bbagen.2016.08.017.
28. Nuzzo D, Picone P, Baldassano S, Caruana L, Messina E, Marino Gammazza A, et al. Insulin resistance as common molecular denominator linking obesity to Alzheimer’s disease. Curr Alzheimers Res. 2015;12(8):723-35. doi: 10.2174/1567205012666151104094754.
29. Gezen-Ak D, Dursun E, Hanağası H, Bilgiç B, Lohman E, Araz ÖS, et al. BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer's disease or mild cognitive impairment. J Alzheimers Dis. 2013;37(1):185-95. doi: 10.3233/JAD-2012-121499.
30. Jiang Y-Q, Wang X-L, Cao X-H, Ye Z-Y, Li L, Cai W-Q. Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer's disease. Brain Res. 2013;1519:105-11. doi: 10.1016/j.brainres.2013.04.040.
31. Valenzuela PL, Castillo-García A, Morales JS, de la Villa P, Hampel H, Emanuele E, et al. Exercise benefits on Alzheimer’s disease: State-of-the-science. Ageing Res Rev. 2020;62:101108. doi: 10.1016/j.arr.2020.101108.
32. Han Y, Wang N, Kang J, Fang Y. β-Asarone improves learning and memory in Aβ 1-42-induced Alzheimer’s disease rats by regulating PINK1-Parkin-mediated mitophagy. Metab Brain Dis. 2020;35:1109-17. doi: 10.1007/s11011-020-00558-7.
33. Nouri K, Feng Y, Schimmer AD. Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy. Cell Death Dis. 2020;11(10):841. doi: 10.1038/s41419-020-02927-0.
34. Kang Y, Fielden LF, Stojanovski D, editors. Mitochondrial protein transport in health and disease. Semin Cell Dev Biol. 2018:Elsevier. doi: 10.1016/j.semcdb.2018.04.009.
35. Braga RR, Crisol BM, Brícola RS, Sant’ana MR, Nakandakari SC, Costa SO, et al. Exercise alters the mitochondrial proteostasis and induces the mitonuclear imbalance and UPRmt in the hypothalamus of mice. Sci Rep. 2021;11(1):3813. doi: 10.1038/s41598-021-82583-4.
36. Barone R, Macaluso F, Sangiorgi C, Campanella C, Marino Gammazza A, Moresi V, et al. Skeletal muscle Heat shock protein 60 increases after endurance training and induces peroxisome proliferator-activated receptor gamma coactivator 1 α1 expression. Sci Rep. 2016;6(1):19781. doi: 10.1038/srep19781.
37. Slavin MB, Kumari R, Hood DA. ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle. Mol Metab. 2022;66:101623. doi: 10.1016/j.molmet.2022.101623.
38. Xin S-H, Tan L, Cao X, Yu J-T, Tan L. Clearance of amyloid beta and tau in Alzheimer’s disease: from mechanisms to therapy. Neurotox Res. 2018;34:733-48. doi: 10.1007/s12035-018-0162-9.
39. Westerheide S. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science. 2013;342(6161):931-. doi: 10.1126/science.1243282.
40. Lee J, Hong S-W, Kwon H, Park SE, Rhee E-J, Park C-Y, et al. Resveratrol, an activator of SIRT1, improves ER stress by increasing clusterin expression in HepG2 cells. Cell Stress Chaperones. 2019;24:825-33. doi: 10.1007/s12192-019-01006-z.
41. Westerheide SD, Anckar J, Stevens Jr SM, Sistonen L, Morimoto RI. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science. 2009;323(5917):1063-6. doi: 10.1126/science.1165344.
42. Wang B, Ge S, Xiong W, Xue Z. Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice. BMC Anesthesiol. 2018;18:1-7. doi: 10.1186/s12871-018-0571-5.
43. Arslan MA, Chikina M, Csermely P, Sőti C. Misfolded proteins inhibit proliferation and promote stress‐induced death in SV40‐transformed mammalian cells. FASEB J. 2012;26(2):766-77. doi: 10.1096/fj.11-197645.
44. Pajares M, Cuadrado A, Rojo AI. Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases. Redox Biol. 2017;11:543-53. doi: 10.1016/j.redox.2016.11.015.
45. Regitz C, Fitzenberger E, Mahn FL, Dußling LM, Wenzel U. Resveratrol reduces amyloid-beta (Aβ1–42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans. Eur J Nutr. 2016;55:741-7. doi: 10.1007/s00394-015-0973-2.
46. Habibi S, Abdi A, Fazelifar S. The Effect of Aerobic Training and Resveratrol on Ferroptosis in a Rat Model of Alzheimer’s Disease. Neurosci J Shefaye Khatam. 2024;1-11.
47. Liao Z-Y, Chen J-L, Xiao M-H, Sun Y, Zhao Y-X, Pu D, et al. The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway. Exp Gerontol. 2017;98:177-83. doi: 10.1016/j.exger.2017.07.003.
48. Broderick TL, Rasool S, Li R, Zhang Y, Anderson M, Al-Nakkash L, et al. Neuroprotective effects of chronic resveratrol treatment and exercise training in the 3xTg-AD mouse model of Alzheimer’s disease. Int J Mol Sci. 2020;21(19):7337. doi: 10.3390/ijms21197337.