한국응용과학기술학회지 (Journal of the Korean Applied Science and Technology)

  • 제37권3호
  • /
  • Pages.418-428
  • /
  • 2020
  • /
  • 1225-9098(pISSN)
  • /
  • 2288-1069(eISSN)
한국응용과학기술학회 (The Korean Society of Applied Science and Technology)
권호 표지
DOI QR코드

DOI QR Code

저항성 운동이 알츠하이머 형질전환 생쥐 뇌의 베타 아밀로이드 대사와 인지기능에 미치는 영향

The effect of resistance exercise on β-amyloid metabolism and cognitive function in a mouse model of Alzheimer's disease

  • 장용철 (한국체육대학교 운동생화학실) ;
  • 구정훈 (한국체육대학교 체육과학연구소)
  • Jang, Yong-Chul (Exercise biochemistry Laboratory, Korea National Sport University) ;
  • Koo, Jung-Hoon (Institute of Sport Science, Korea National Sport University)
  • 투고 : 2020.04.01
  • 심사 : 2020.06.19
  • 발행 : 2020.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

본 연구는 알츠하이머(Alzheimer's disease: AD) 형질전환 생쥐를 대상으로 저항성 운동(resistance exercise: RE)이 해마의 베타 아밀로이드(β-amyloid: Aβ) 단백질 대사, 신경세포사멸 및 인지기능에 미치는 영향을 확인하는데 목적이 있다. AD 비 형질전환 생쥐(non-transgenic: non-tg, n=14)와 형질전환 생쥐(transgenic: Tg, n=14)를 무선 배정하여 비 형질전환 생쥐 대조군 (non-tg-control: NTC, n=7), 비 형질전환 생쥐 저항성 운동군(non-tg-RE: NTRE, n=7), 형질전환 대조군(tg-control: TC, n=7) 및 형질전환 저항성 운동군(tg-RE: TRE, n=7)으로 구분하였다. RE는 특수 제작한 사다리 저항성 운동 기구를 사용하여 점진적으로 set 수를 증가시켜 총 8주간 실시하였다. 운동 후 인지기능 능력을 평가하기 위한 수중미로검사와 Aβ 단백질 대사, 신경세포사멸 지표 및 SIRT1/PGC-1α 단백질 발현 수준을 확인하였다. 수중미로검사 결과 거리와 시간 모두 TC 집단에서 유의하게 증가 되었지만 RE를 실시한 TRE 집단에서 거리와 시간이 감소 되어 인지능력이 개선된 것으로 확인되었다. 또한, TC 집단에서 증가된 Aβ 단백질 발현은 RE를 통해 감소하는 것으로 나타났다. 신경세포사멸 관련 단백질인 Bcl-2/Bax ratio는 TC 집단에서 유의하게 감소되어 신경세포사멸이 증가 된 것으로 나타났지만 RE는 Bcl-2/Bax ratio을 증가시켜 신경세포사멸을 감소시킨 것으로 확인되었다. TC 집단에서 증가된 BACE1 및 ROCK1과 감소된 ADAM10과 RARβ 단백질 발현은 RE를 통해 감소되거나 증가 된 것으로 나타났고, SIRT1/PGC-1α 단백질 발현은 TC 집단에서 감소 되었지만 RE를 통해 증가 된 것으로 나타났다. 따라서 8주간의 RE는 AD의 병리학적 특징인 Aβ 단백질 발현을 감소시키고 관련 생성 기전들을 조절하여(SIRT1/PGC-1α 기전 활성, 아밀로이드 생성기전 억제, 비-아밀로이드 생성기전 활성) 신경세포사멸 억제시키고 결과적으로 인지기능을 개선 시킬 수 있는 효과적인 운동 방법이라고 생각된다.

The aim of this study was to investigate the effect of resistance exercise(RE) on beta-amyloid(Aβ) metabolism, neuronal cell death, and cognitive function in the transgenic mice model of Alzheimer's disease(AD). Fourteen transgenic(tg) mice and fourteen non-transgenic(non-tg) mice were divided into four groups: (1)non-tg-control(NTC, n=7) (2)non-tg-RE(NTRE, n=7) (3)tg-control(TC, n=7), and (4)tg-RE(TRE, n=7). The groups with RE were performed to progressive RE on ladder equipment for 8 weeks. The groups with RE were performed to progressive RE on ladder equipment for 8 weeks. After then, the cognitive function was measured by using the water maze test, and Aβ metabolism-related proteins, neuronal cell death, and SIRT1/PGC-1α pathway were also measured. Here, we found escape latency and time were significantly increased in the TC compared to the NTC group, but it was significantly reduced in the TRE group, indicating RE may ameliorate cognitive dysfunction. Next, we found an increased in Aβ protein of TC compared to NTC, but it was significantly reduced in the TRE group following RE. In neuronal cell death, Bcl-2 was also significantly decreased and Bax was significantly increased in the TC compared to the NTC group, but RE can increase Bcl-2 and reduce Bax, which may elevate the ratio of Bcl-2/Bax. We further found a decrease in the level of ADAM10 and RARβ protein was significantly increased whereas increased in ROCK1 and BACE1 expression level was significantly reduced following RE in the TRE compared to the TC group. In addition, the level of SIRT1/PGC-1α proteins was decreased in the TC group compared to NTC group, but, these markers were significantly increased in the TRE group following RE. Therefore, our finding indicated that RE may ameliorate cognitive deficits by reducing Aβ protein and neuronal cell death via regulating SIRT1/PGC-1α, amyloidogenic pathway, and non-amyloidogenic pathway, which may play a role in an effective strategy for AD.

키워드

참고문헌

  1. H. J. Nam, S. H. Hwang, Y. J. Kim, K. W. Kim, "Korean Dementia observatory 2018", Seoul Central Dementia Center, Ministry of Health and Welfare, (2018).
  2. D. J. Selkoe, J. Hardy, "The amyloid hypothesis of Alzheimer's disease at 25 years", EMBO molecular medicine, Vol.8, No.6 pp. 595-608, (2016). https://doi.org/10.15252/emmm.201606210
  3. G Botteri, L Salvado, A. Guma, Lee D. Hamilton, P. J. Meakin, G. Montagut, M. L. J. Ashford, V. Ceperuelo-Mallafre, S. Fernandez-Veledo, J. Vendrell, M. Calderon-Dominguez, D. Serra, L. Herrero, J. Pizarro, E. Barroso, X. Palomer, M. Vazquez-Carrera, "The BACE1 product $sAPP{\beta}$ induces ER stress and inflammation and impairs insulin signaling", Metabolism, Vol.85, pp. 59-75, (2018). https://doi.org/10.1016/j.metabol.2018.03.005
  4. P. H. Reddy, X. Yin, M. Manczak, S. Kumar, J. A. Pradeepkiran, M. Vijayan, A. P. Reddy, "Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease", Human molecular genetics, Vol.27, No.14 pp. 2502-2516, (2018). https://doi.org/10.1093/hmg/ddy154
  5. R. J. Mullins, T. C. Diehl, C. W. Chia, D. Kapogiannis, "Insulin resistance as a link between Amyloid-Beta and Tau pathologies in Alzheimer's disease", Frontiers in Aging Neuroscience, Vol.9, pp. 118, (2017). https://doi.org/10.3389/fnagi.2017.00118
  6. V. Sharma, P. Nagu, R. Thakur, P. Sharma, H. Kumar, "Amyloid Beta Mediated Mitochondrial Dysfunction in Alzheimer's disease: A Mini Review", Current Pharma Research, Vol.9, No.3 pp. 2981-2990, (2019). https://doi.org/10.33786/JCPR.2019.v09i03.017
  7. W. H. Organization, "Risk reduction of cognitive decline and dementia: WHO guidelines", in Risk reduction of cognitive decline and dementia: WHO guidelines. pp. 401-401, (2019).
  8. L. A. van der Kleij, E. T. Petersen, H. R Siebner, J. Hendrikse, K. S. Frederiksen, N. A. Sobol, S. G. Hasselbalch, E. Garde, "The effect of physical exercise on cerebral blood flow in Alzheimer's disease", NeuroImage: Clinical, Vol20, pp. 650-654, (2018). https://doi.org/10.1016/j.nicl.2018.09.003
  9. T. Matsui, H. Omuro, Y. F. Liu, M. Soya, T. Shima, B. S. McEwen, H. Soya, "Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity", Proceedings of the National Academy of Sciences, Vol114, No.24 pp. 6358-6363, (2017). https://doi.org/10.1073/pnas.1702739114
  10. H. C. Park, J. U. Cheon, "Effects of 16-week Combined Exercise on Dementia, Depression, and Cognitive Function in Elderly Women", Journal of the Korean Applied Science and Technology, Vol36, No.2 pp. 456-467, (2019). https://doi.org/10.12925/JKOCS.2019.36.2.456
  11. F. Liang, T. Huang, B. Li, Y. Zhao, X. Zhang, B. Xu, "High-intensity interval training and moderate-intensity continuous training alleviate ${\beta}$-amyloid deposition by inhibiting NLRP3 inflammasome activation in APPswe/PS1dE9 mice", NeuroReport, Vol31, No.5 pp. 425-432, (2020). https://doi.org/10.1097/wnr.0000000000001429
  12. B. Zeng, G. Zhao, H. L. Liu, "The differential effect of treadmill exercise intensity on hippocampal soluble $a{\beta}$ and lipid metabolism in APP/PS1 mice", Neuroscience, Vol430, pp. 73-81, (2020). https://doi.org/10.1016/j.neuroscience.2020.01.005
  13. L. Woost, P. L. Bazin, M. Taubert, R. Trampel, C. L. Tardif, A. Garthe, G. Kempermann, U. Renner, G. Stalla, D. V. M. Ott, V. Rjosk, H. Obrig, A. Villringer, E. Roggenhofer, T. A. Klein, "Physical exercise and spatial training: a longitudinal study of effects on cognition, growth factors, and hippocampal plasticity", Scientific reports, Vol8, No.1 pp. 1-13, (2018). https://doi.org/10.1038/s41598-017-17765-5
  14. J. H. Koo, E. B. Kang, Y. S. Oh, D. S. Yang, J. Y. Cho, "Treadmill exercise decreases amyloid-${\beta}$ burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer's disease", Experimental neurology, Vol288, No.5 pp. 142-152, (2017). https://doi.org/10.1016/j.expneurol.2016.11.014
  15. C. McGlory, M. C. Devries, S. M. Phillips, "Skeletal muscle and resistance exercise training; the role of protein synthesis in recovery and remodeling", Journal of Applied Physiology, Vol122, No.3 pp. 541-548, (2017). https://doi.org/10.1152/japplphysiol.00613.2016
  16. E. M. P. ortugal, P. G. Vasconcelos, R. Souza, E. Lattari, R. S. Monteiro-Junior, S. Machado, A. C. Deslandes, "Aging process, cognitive decline and Alzheimers disease: can strength training modulate these responses?", CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), Vol14, No.9 pp. 1209-1213, (2015). https://doi.org/10.2174/1871527315666151111121749
  17. K. J. Marston, M. J. Newton, B. M. Brown, S. R. Rainey-Smith, S. Bird, R. N. Martins, J. J. Peiffer., "Intense resistance exercise increases peripheral brain-derived neurotrophic factor", Journal of science and medicine in sport, Vol20, No.10 pp. 899-903, (2017). https://doi.org/10.1016/j.jsams.2017.03.015
  18. K. M. Broadhouse, M. F. Singh, C. Suo, N. Gates, W. Wen, H. Brodaty, N. Jain, G. C. Wilson, J. Meiklejohn, N. Singh, B. T. Baune, M. Baker, N. Foroughi, Y. Wang, N. Kochan, K. Ashton, M. Brown, Z. Li, Y. Mavros, P. S. Sachdev, M. J. Valenzuela, "Hippocampal plasticity underpins long-term cognitive gains from resistance exercise in MCI", NeuroImage: Clinical, Vol25, pp. 102-182, (2020).
  19. M. C. Chang, A. Y. Lee, S. Kwak, S. G. Kwak, "Effect of resistance exercise on depression in mild Alzheimer disease patients with sarcopenia", The American Journal of Geriatric Psychiatry, Vol28, No.5 pp. 587-589, (2019). https://doi.org/10.1016/j.jagp.2019.07.013
  20. S. E. Lamb, D. Mistry, S. Alleyne, N. Atherton, D. Brown, B. Copsey, S. Dosanjh, S. Finnegan, B. Fordham, F. Griffiths, S. Hennings, I. Khan, K. Khan, R. Lall, S. Lyle, V. Nichols, S. Petrou, P. Zeh, B. Sheehan, "Aerobic and strength training exercise programme for cognitive impairment in people with mild to moderate dementia: the DAPA RCT", Health Technology Assessment, Vol22, No.28 pp. 1-202, (2017).
  21. T. M. Vital, S. S. S. Hernandez, R. V. Pedroso, C. V. L Teixeira, M. Garuffi, A. M. Stein, J. L. R. Costa, F. Stella, "Effects of weight training on cognitive functions in elderly with Alzheimer's disease", Dementia & neuropsychologia, Vol6, No.4 pp. 253-259, (2015).
  22. J. P. Cleary, D. M. Walsh, J. J. Hofmeister, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH, "Natural oligomers of the amyloid-${\beta}$ protein specifically disrupt cognitive function", Nature neuroscience, Vol8, No.1 pp. 79-84, (2005). https://doi.org/10.1038/nn1372
  23. L. R. Clark, A. M. Racine, R. L. Koscik, O. C. Okonkwo, C. D. Engelman, C. M. Carlsson, S. Asthana, B. B. Bendlin, R. Chappell, C. R. Nicholas, H. A. Rowley, J. M. Oh, B. P. Hermann, M. A. Sager, B. T. Christian, S. C. Johnson, "Beta-amyloid and cognitive decline in late middle age: Findings from the Wisconsin Registry for Alzheimer's Prevention study", Alzheimer's & Dementia, Vol12, No.7 pp. 805-814, (2016). https://doi.org/10.1016/j.jalz.2015.12.009
  24. H. S. Um, E. B. Kang, J. H. Koo, H. T. Kim, Jin-Lee, E. J. Kim, C. H. Yang, G. Y. An, I. H. Cho, J. Y. Cho, "Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease", Neuroscience research, Vol69, No.2 pp. 161-173, (2011). https://doi.org/10.1016/j.neures.2010.10.004
  25. F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia, R. Malinow, "APP processing and synaptic function", Neuron, Vol37, No.6 pp. 925-937, (2003). https://doi.org/10.1016/S0896-6273(03)00124-7
  26. G. Marwarha, S. Raza, C. Meiers, O. Ghribi, "Leptin attenuates BACE1 expression and amyloid-${\beta}$ genesis via the activation of SIRT1 signaling pathway", Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, Vol1842, No.9 pp. 1587-1595, (2014). https://doi.org/10.1016/j.bbadis.2014.05.015
  27. H. R. Lee, H. K. Shin, S. Y. Park, H. Y. Kim, W. S. Lee, B. Y. Rhim, K. W. Hong, C. D. Kim, "Cilostazol suppresses ${\beta}$-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-${\beta}$", Journal of neuroscience research, Vol92, No.11 pp. 1581-1590., (2014). https://doi.org/10.1002/jnr.23421
  28. Y. I. Kim, D. P. Ok, S. Y. Cho, "The Effects of Regular Taekwondo Exercise on Brain wave activation and Neurotrophic Factors in Undergraduate male students", Journal of the Korean Applied Science and Technology, Vol35, No.2 pp. 412-422., (2018).
  29. D. Y. Hwang, K. R. Chae, T .S. Kang, J. H. Hwang, C. H. Lim, H. K. Kang, J. S. Goo, M. R. Lee, H. J. Lim, S. H. Min, J. Y. Cho, J. T. Hong, C. W. Song, S. G. Paik, J. S. Cho, Y. K. Ki, "Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease", Federation of American Societies for Experimental Biology, Vol16 No.8 pp. 805-813., (2002). https://doi.org/10.1096/fj.01-0732com
  30. L. W. Bradford, "Problems of ethics and behavior in the forensic sciences", Journal of forensic sciences, Vol21, No.2 pp. 763-768., (1976). https://doi.org/10.1520/JFS10557J
  31. K. Bromley-Brits, Y. Deng, W. Song, "Morris water maze test for learning and memory deficits in Alzheimer's disease model mice", Journal of Visualized Experiments, Vol53, e2920, (2011).