한국응용과학기술학회지 (Journal of the Korean Applied Science and Technology)

  • 제41권1호
  • /
  • Pages.58-68
  • /
  • 2024
  • /
  • 1225-9098(pISSN)
  • /
  • 2288-1069(eISSN)
한국응용과학기술학회 (The Korean Society of Applied Science and Technology)
권호 표지
DOI QR코드

DOI QR Code

트레드밀 운동 및 환경강화가 알츠하이머 질환 동물 모델의 인지기능, 근 기능 및 밀착연접 단백질 수준에 미치는 영향

The Effect of Treadmill Exercise and Environmental Enrichment on Cognitive Function, Muscle Function, and Levels of tight junction protein in an Alzheimer's Disease Animal Model

  • 엄현섭 (건양대학교 스포츠의학과) ;
  • 정종환 (한국체육대학교 체육학과) ;
  • 김태경 (한국체육대학교 체육과학연구소) ;
  • 전유정 (한국체육대학교 운동건강관리학과) ;
  • 조준용 (한국체육대학교 운동건강관리학과) ;
  • 구정훈 (한국체육대학교 운동건강관리학과)
  • Hyun-Seob Um (Sport Medicine, Kon Yang University) ;
  • Jong-Hwan Jung (Physical Education, Korea National Sport University) ;
  • Tae-Kyung Kim (Sport Science Institute, Korea National Sport University) ;
  • Yoo-Joung Jeon (Exercise Training for Health care and Management, Korea National Sport University) ;
  • Joon-Yong Cho (Exercise Training for Health care and Management, Korea National Sport University) ;
  • Jung-Hoon Koo (Exercise Training for Health care and Management, Korea National Sport University)
  • 투고 : 2024.01.25
  • 심사 : 2024.02.23
  • 발행 : 2024.02.28
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

본 연구의 목적은 알츠하이머질환(Alzheimer's disease: AD) 동물 모델을 대상으로 트레드밀 운동(Treadmill exercise: TE)과 환경강화(environmental enrichment: EE) 처치가 인지기능, 근 기능, 및 밀착연접 단백질 발현에 미치는 영향을 확인하는데 있다. AD 동물 모델을 제작하기 위해 aluminum chloride(AlCl3)를 90일간(40mg/kg/하루) 투여 하였으며 동시에 TE(10-12m/min, 40-60min/day) 혹은 EE에 노출시켰다. 그 결과 AlCl3 투여에 의한 인지기능 저하와 근 기능 감소가 TE와 EE에 의해 완화된 것으로 나타났다. 또한, TE와 EE는 AD 질환에서 나타나는 β-amyloid(Aβ), alpha-synuclein 및 tumor necrosis factor-α(TNF-α) 단백질의 발현 증가를 감소시킨 것으로 나타났다. 게다가 TE와 EE는 AlCl3 투여에 의해 감소된 밀착연접 단백질(Occludin, Claudin-5 및 ZO-1)의 발현을 통계적으로 유의하게 증가시킨 것으로 나타났다. 마지막으로 Aβ 단백질과 밀착연접 단백질과의 상관분석을 실시한 결과 부적 상관관계(Occludin: r=-0.853, p=0.001; Claudin-5 : r=-0.352, p=0.915; ZO-1 : r=-0.424, p=0.0390)로 나타났다. 따라서 이를 종합해 보면 TE 혹은 EE 처치는 AD에 나타나는 병리학적 특징들을 일부 완화시켜 인지기능과 근 기능을 일부 개선 시킬 수 있는 효과적인 운동 방법이라고 생각된다.

The purpose of this study was to investigate the effects of treadmill exercise treadmill exercise (TE) and environmental enrichment (EE) interventions on cognitive function, muscle function, and the expression of tight junction proteins in an Alzheimer's disease (AD) animal model. To create the AD animal model, aluminum chloride (AlCl3) was administered for 90 days (40mg/kg/day), while simultaneously exposing the animals to TE (10-12m/min, 40-60min/day) or EE. The results showed that cognitive impairment and muscle dysfunction induced by AlCl3 administration were alleviated by TE and EE. Furthermore, TE and EE reduced the increased expression of β-amyloid(Aβ), alpha-synuclein, and tumor necrosis factor-α (TNF-α) proteins observed in AD pathology. Additionally, TE and EE significantly increased the expression of decreased adhesive adjacent proteins (Occludin, Claudin-5, and ZO-1) induced by AlCl3 administration. Lastly, correlation analysis between Aβ protein and tight junction proteins showed negative correlations (Occludin: r=-0.853, p=0.001; Claudin-5: r=-0.352, p=0.915; ZO-1: r=-0.424, p=0.0390). In conclusion, TE or EE interventions are considered effective exercise methods that partially alleviate pathological features of AD, improving cognitive and muscle function.

키워드

과제정보

이 논문은 2021년 대한민국 교육부와 한국연구재단의 지원을 받아 수행된 연구임 (NRF-2021S1A5A8065404)

참고문헌

  1. Z. Jaunmuktane, S. Mead, M. Ellis, J. D. F. Wadsworth, A. J. Nicoll, J. Kenny, F. Launchbury, J. Linehan, A. Richard-Loendt, A. S. Walker, P. Rudge, J. Collinge, S. Brandner, "Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy", Nature, Vol.525, No.7568 pp. 247, 2015. 
  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. K. Govindpani, L. G. McNamara, N. R. Smith, C. Vinnakota, H. J. Waldvogel, R. L. Faul, A. Kwakowsky, "Vascular Dysfunction in Alzheimer's Disease: A Prelude to the Pathological Process or a Consequence of It?", Journal of clinical medicine, Vol.8, No.5 pp. 651, (2019). 
  4. M. Brkic, et al, S. Balusu, E. V. Wonterghem, N. Gorle, I. Benilova, A. Kremer, I. V. Hove, L. Moons, B. D. Strooper, S .Kanazir, C. Libert, R. E. Vandenbroucke, "Amyloid β oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases", Journal of Neuroscience, Vol.35, No.37 pp. 12766-12778, (2015).  https://doi.org/10.1523/JNEUROSCI.0006-15.2015
  5. Y. Chan, W. Chen, W. Wan, Y. Chen, Y. Li, C. Zhang, "Aβ1-42 oligomer induces alteration of tight junction scaffold proteins via RAGE-mediated autophagy in bEnd. 3 cells", Experimental cell research, Vol.369, No.2 pp. 266-274, (2018).  https://doi.org/10.1016/j.yexcr.2018.05.025
  6. E. Frith, P. D. Loprinzi, "Physical activity is associated with higher cognitive function among adults at risk for Alzheimer's disease. Complementary therapies in medicine", Vol.36, pp. 46-49, (2018).  https://doi.org/10.1016/j.ctim.2017.11.014
  7. S. H. Choi, E. Bylykbashi, Z. K. Chatila, S. W. Lee, B. Pulli, G. D. Clemenson, R. E. Tanzi, "Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model", Science, Vol.361, No.6406 eaan8821, (2018). 
  8. M. Azimi, R. Gharakhanlou, N. Naghdi, D. Khodadadi, S. Heysieattalab, "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, Vol.102, pp. 78-88, (2018).  https://doi.org/10.1016/j.peptides.2017.12.027
  9. X. Zhang, Q. He, T. Huang, N. Zhao, F. Liang, B. Xu, X. Chen, T. Li, J. Bi, "Treadmill exercise decreases Aβ deposition and counteracts cognitive decline in APP/PS1 mice, possibly via hippocampal microglia modifications", Frontiers in aging neuroscience, Vol.11, pp. 78, (2019). 
  10. L. Serra, R. Perri, L. Fadda, A. Padovani, S. Lorusso, C. Pettenati, G. A. Carlesimo, "Relationship between cognitive impairment and behavioural disturbances in Alzheimer's disease patients", Behavioural neurology, Vol.23, No.3 pp. 123-130, (2010).  https://doi.org/10.1155/2010/528694
  11. M. S. Beeri, S. E. Leugrans, O. Delbono, D. A. Bennett, A. S. Buchman, "Sarcopenia is associated with incident Alzheimer's dementia, mild cognitive impairment, and cognitive decline", Journal of the American Geriatrics Society, Vol.69, No.7 pp. 1826-1835, (2021).  https://doi.org/10.1111/jgs.17206
  12. C. M. Yuede, B. F. Timson, J. C. Hettinger, K. M. Yuede, H. M. Edwards, J. E. Lawson, S. D. Zimmerman, J. R. Cirrito, "Interactions between stress and physical activity on Alzheimer's disease pathology", Neurobiology of stress, Vol.8, pp. 158-171, (2018).  https://doi.org/10.1016/j.ynstr.2018.02.004
  13. G. P. Cortese, A. Olin, K. O'Riordan, R. Hullinger, C. Burger, "Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity", Neurobiology of aging, Vol.63, pp. 1-11, (2018).  https://doi.org/10.1016/j.neurobiolaging.2017.11.004
  14. Clemenson, GD, Gage FH, Stark CE, Environmental Enrichment and Neuronal Plasticity, The Oxford Handbook of Developmental Neural Plasticity, (2018). 
  15. Y. Selvi, H. S. Gergerlioglu, N. Akbaba, M. Oz, A. Kandeger, E. A. Demir, F. H. Yerlikaya, K. E. Nurullahoglu-Atalik, "Impact of enriched environment on production of tau, amyloid precursor protein and, amyloid-β peptide in high-fat and high-sucrose-fed rats", Acta neuropsychiatrica, Vol.29, No.5 pp. 291-298, (2017).  https://doi.org/10.1017/neu.2016.63
  16. H. Xu, M. M. Rajsombath, P. Weikop, D. J. Selkoe, "Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloidβ", EMBO molecular medicine, Vol.10, No.9 pp. e8931, (2018). 
  17. J. Balthazar, N. M. Schowe, G. C. Cipolli, H. S. Buck, T. A. Viel, "Enriched Environment Significantly Reduced Senile Plaques in a Transgenic Mice Model of Alzheimer's Disease, Improving Memory", Frontiers in aging neuroscience, Vol.10, 288, (2018). 
  18. H. S. Um, E. B. Kang, J. H. Koo, H. T. Kim, E. J. Kim, C. H. Yang, J. Y. Cho, "Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease", Neuroscience research, Vol.69, No.2 pp. 161-173, (2011).  https://doi.org/10.1016/j.neures.2010.10.004
  19. S. Madiha, Z. Batool, S. Tabassum, L. Liaquat, S. Sadir, T. Perveen, S. Haider, "Therapeutic effects of Curcuma longa against rotenone-induced gross motor skill deficits in rats", Pakistan Journal of Zoology, Vol.50, No.4 pp. 1245-1256, (2018).  https://doi.org/10.17582/journal.pjz/2018.50.4.1245.1256
  20. M. Mold, C. Linhart, J. Gomez-Ramirez, A. Villegas-Lanau, C. Exley, "Aluminum and amyloid-β in familial Alzheimer's disease", Journal of Alzheimer's Disease, Vol.73, No.4 pp. 1627-1635, (2020).  https://doi.org/10.3233/JAD-191140
  21. A. M. Elfiky, A. A. Mahmoud, H. A. Elreedy, K. S. Ibrahim, M. A. Ghazy, "Quercetin stimulates the non- amyloidogenic pathway via activation of ADAM10 and ADAM17 gene expression in aluminum chloride-induced Alzheimer's disease rat model", Life Sciences, Vol.285, 119964, (2021). 
  22. J. H. Jeong, D. H. Choi, J. K. Lee, J. Y. Cho, J. H. Jeong, D. H. Choi, J. Y. Cho, "Effect of Endurance Exercise and MitoQ Intake on Tau Hyperphosphorylation, Oxidative Stress, Antioxidant Modulating Factors, Mitochondrial Function, and Cognitive Function in Alcl3-Induced Alzheimer's Disease Animal Model", Exercise Science, Vol.30, No.3 pp. 396-406, (2021).  https://doi.org/10.15857/ksep.2021.30.3.396
  23. M. Nakano, K. Kubota, S. Hashizume, E. Kobayashi, T. S. Chikenji, Y. Saito, M. Fujimiya, "An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus", Brain, Behavior, & Immunity-Health, Vol.9, 100149, (2020). 
  24. D. Takagi, H. Hirano, Y. Watanabe, A. Edahiro, Y. Ohara, H. Yoshida, S. Hironaka, "Relationship between skeletal muscle mass and swallowing function in patients with Alzheimer's disease", Geriatrics & Gerontology International, Vol.17, No.3 pp. 402-409, (2017).  https://doi.org/10.1111/ggi.12728
  25. Y. Ogawa, Y. Kaneko, T. Sato, S. Shimizu, H. Kanetaka, H. Hanyu, "Sarcopenia and muscle functions at various stages of Alzheimer disease", Frontiers in neurology, Vol.9, 710, (2018). 
  26. C. H. Turkseven, B. Buyukakilli, E. Balli, D. Yetkin, M. E. Erdal, S. G. Yilmaz, L. Sahin, "Effects of Huperzin-A on the Beta-amyloid accumulation in the brain and skeletal muscle cells of a rat model for Alzheimer's disease", Life sciences, Vol.184, pp. 47-57, (2017).  https://doi.org/10.1016/j.lfs.2017.07.012
  27. Y. Zhao, F. Shen, M. Gong, L. Jin, X. Ren, K.. Liu, J. Lu, "Lifelong treadmill training improves muscle function detected by a modified grip strength test during aging in BALB/c mice", Life sciences, Vol.251, 117603, (2020). 
  28. Y. Luo, F. Niu, Z. Sun, W. Cao, X. Zhang, D. Guan, Y. Xu, "Altered expression of Aβ metabolism-associated molecules from d-galactose/AlCl3 induced mouse brain", Mechanisms of ageing and development, Vol.130, No,4 pp. 248-252, (2009).  https://doi.org/10.1016/j.mad.2008.12.005
  29. J. B. oledo, P. Gopal, K. Raible, D. J. Irwin, J. Brettschneider, S. edor, J. Q rojanowski, "Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology", Acta neuropathologica, Vol.131, pp. 393-409, (2016).  https://doi.org/10.1007/s00401-015-1526-9
  30. M. D. Sweeney, A. P. Sagare, B. V. Zlokovic, "Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders", Nature Reviews Neurology, Vol.14, No.3 pp. 133, (2018). 
  31. Y. Yamazaki, M. Shinohara, M. Shinohara, A. Yamazaki, M. E. Murray, A. M. Liesinger, M. G. Heckman, E. R. Lesser, J. E. Parisi, R. C. Petersen, D. W. Dickson, T. Kanekiyo, G. Bu, "Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression", Brain, Vol.142, No.4 pp. 1077-1092, (2019).  https://doi.org/10.1093/brain/awz011
  32. H. Zetterberg, J. M. Schott, "Biomarkers for Alzheimer's disease beyond amyloid and tau", Nature medicine, Vol.25, No.2 pp. 201, 2019. 
  33. H. Hourfar, F. Aliakbari, S. R. Aqdam, Z. Nayeri, H. Bardania, D. E. Otzen, D. Morshedi, "The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells", International Journal of Biological Macromolecules, Vol.229, pp. 305-320, (2023). https://doi.org/10.1016/j.ijbiomac.2022.12.134