DOI QR코드

DOI QR Code

Raw Inonotus obliquus polysaccharide counteracts Alzheimer's disease in a transgenic mouse model by activating the ubiquitin-proteosome system

  • Shumin Wang (School of Basic Medicine, Dali University) ;
  • Kaiye Dong (Department of Ophthalmology, The First Affiliated Hospital of Dali University) ;
  • Ji Zhang (College of Clinical Medicine, Dali University) ;
  • Chaochao Chen (College of Clinical Medicine, Dali University) ;
  • Hongyan Shuai (School of Basic Medicine, Dali University) ;
  • Xin Yu (School of Basic Medicine, Dali University)
  • 투고 : 2023.06.05
  • 심사 : 2023.09.14
  • 발행 : 2023.12.01

초록

BACKGROUND/OBJECTIVES: Inonotus obliquus has been used as antidiabetic herb around the world, especially in the Russian and Scandinavian countries. Diabetes is widely believed to be a key factor in Alzheimer's disease (AD), which is widely considered to be type III diabetes. To investigate whether I. obliquus can also ameliorate AD, it would be interesting to identify new clues for AD treatment. We tested the anti-AD effects of raw Inonotus obliquus polysaccharide (IOP) in a mouse model of AD (3×Tg-AD transgenic mice). MATERIALS/METHODS: SPF-grade 3×Tg-AD mice were randomly divided into three groups (Control, Metformin, and raw IOP groups, n = 5 per group). β-Amyloid deposition in the brain was analyzed using immunohistochemistry for AD characterization. Gene and protein expression of pertinent factors of the ubiquitin-proteasome system (UPS) was determined using real-time quantitative polymerase chain reaction and Western blotting. RESULTS: Raw IOP significantly reduced the accumulation of amyloid aggregates and facilitated UPS activity, resulting in a significant reduction in AD-related symptoms in an AD mouse model. The presence of raw IOP significantly enhanced the expression of ubiquitin, E1, and Parkin (E3) at both the mRNA and protein levels in the mouse hippocampus. The mRNA level of ubiquitin carboxyl-terminal hydrolase isozyme L1, a key factor involved in UPS activation, also increased by approximately 50%. CONCLUSIONS: Raw IOP could contribute to AD amelioration via the UPS pathway, which could be considered as a new potential strategy for AD treatment, although we could not exclude other mechanisms involved in counteracting AD processing.

키워드

과제정보

We thank Dr. Su Yingzhen, Kunming University, for helpful discussions on topics related to this work and Dr.Gong Zhiting, School of Basic Medical Science, Dali University, for providing the 3× Tg-AD mice model.

참고문헌

  1. Rusek M, Pluta R, Ulamek-Koziol M, Czuczwar SJ. Ketogenic diet in Alzheimer's disease. Int J Mol Sci 2019;20:3892.
  2. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885-90. https://doi.org/10.1016/S0006-291X(84)80190-4
  3. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016;8:595-608. https://doi.org/10.15252/emmm.201606210
  4. Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biol 2018;14:450-64. https://doi.org/10.1016/j.redox.2017.10.014
  5. Bachiller S, Alonso-Bellido IM, Real LM, Perez-Villegas EM, Venero JL, Deierborg T, Armengol JA, Ruiz R. The ubiquitin proteasome system in neuromuscular disorders: moving beyond movement. Int J Mol Sci 2020;21:6429.
  6. Hong L, Huang HC, Jiang ZF. Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer's disease. Neurol Res 2014;36:276-82. https://doi.org/10.1179/1743132813Y.0000000288
  7. Lopez Salon M, Pasquini L, Besio Moreno M, Pasquini JM, Soto E. Relationship between beta-amyloid degradation and the 26S proteasome in neural cells. Exp Neurol 2003;180:131-43. https://doi.org/10.1016/S0014-4886(02)00060-2
  8. Verheijen BM, Stevens JA, Gentier RJ, van 't Hekke CD, van den Hove DL, Hermes DJ, Steinbusch HW, Ruijter JM, Grimm MO, Haupenthal VJ, et al. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging 2018;72:62-71. https://doi.org/10.1016/j.neurobiolaging.2018.08.011
  9. Lee MW, Hur H, Chang KC, Lee TS, Ka KH, Jankovsky L. Introduction to distribution and ecology of sterile conks of Inonotus obliquus. Mycobiology 2008;36:199-202. https://doi.org/10.4489/MYCO.2008.36.4.199
  10. Lu Y, Jia Y, Xue Z, Li N, Liu J, Chen H. Recent developments in Inonotus obliquus (Chaga mushroom) polysaccharides: isolation, structural characteristics, biological activities and application. Polymers (Basel) 2021;13:1441.
  11. Arata S, Watanabe J, Maeda M, Yamamoto M, Matsuhashi H, Mochizuki M, Kagami N, Honda K, Inagaki M. Continuous intake of the Chaga mushroom (Inonotus obliquus) aqueous extract suppresses cancer progression and maintains body temperature in mice. Heliyon (Lond) 2016;2:e00111.
  12. Giridharan VV, Thandavarayan RA, Konishi T. Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom. Food Funct 2011;2:320-7. https://doi.org/10.1039/c1fo10037h
  13. Han Y, Nan S, Fan J, Chen Q, Zhang Y. Inonotus obliquus polysaccharides protect against Alzheimer's disease by regulating Nrf2 signaling and exerting antioxidative and antiapoptotic effects. Int J Biol Macromol 2019;131:769-78. https://doi.org/10.1016/j.ijbiomac.2019.03.033
  14. Jeong JH, Kim SH, Park MN, Park JY, Park HY, Song CE, Moon JH, Choi A, Kim KD, Lee NS, et al. Water extract of mixed mushroom mycelia grown on a solid barley medium is protective against experimental focal cerebral ischemia. Curr Issues Mol Biol 2021;43:365-83. https://doi.org/10.3390/cimb43010030
  15. Kou RW, Han R, Gao YQ, Li D, Yin X, Gao JM. Anti-neuroinflammatory polyoxygenated lanostanoids from Chaga mushroom Inonotus obliquus. Phytochemistry 2021;184:112647.
  16. Lee MG, Kwon YS, Nam KS, Kim SY, Hwang IH, Kim S, Jang H. Chaga mushroom extract induces autophagy via the AMPK-mTOR signaling pathway in breast cancer cells. J Ethnopharmacol 2021;274:114081.
  17. Li Y, Zhou Y, Wu J, Li J, Yao H. Phelligridin D from Inonotus obliquus attenuates oxidative stress and accumulation of ECM in mesangial cells under high glucose via activating Nrf2. J Nat Med 2021;75:1021-9. https://doi.org/10.1007/s11418-021-01534-w
  18. Szychowski KA, Skora B, Pomianek T, Gminski J. Inonotus obliquus - from folk medicine to clinical use. J Tradit Complement Med 2020;11:293-302. https://doi.org/10.1016/j.jtcme.2020.08.003
  19. Zou CX, Dong SH, Hou ZL, Yao GD, Lin B, Huang XX, Song SJ. Modified lanostane-type triterpenoids with neuroprotective effects from the fungus Inonotus obliquus. Bioorg Chem 2020;105:104438.
  20. Zou CX, Wang XB, Lv TM, Hou ZL, Lin B, Huang XX, Song SJ. Flavan derivative enantiomers and drimane sesquiterpene lactones from the Inonotus obliquus with neuroprotective effects. Bioorg Chem 2020;96:103588.
  21. Zhu ZY, Liu XC, Fang XN, Sun HQ, Yang XY, Zhang YM. Structural characterization and anti-tumor activity of polysaccharide produced by Hirsutella sinensis. Int J Biol Macromol 2016;82:959-66. https://doi.org/10.1016/j.ijbiomac.2015.10.075
  22. Liu M, Liu Y, Cao MJ, Liu GM, Chen Q, Sun L, Chen H. Antibacterial activity and mechanisms of depolymerized fucoidans isolated from Laminaria japonica. Carbohydr Polym 2017;172:294-305. https://doi.org/10.1016/j.carbpol.2017.05.060
  23. Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim MO. Neuroprotective effect of fisetin against amyloid-beta-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol Neurobiol 2017;54:2269-85. https://doi.org/10.1007/s12035-016-9795-4
  24. Liu Y, Hettinger CL, Zhang D, Rezvani K, Wang X, Wang H. The proteasome function reporter GFPu accumulates in young brains of the APPswe/PS1dE9 Alzheimer's disease mouse model. Cell Mol Neurobiol 2014;34:315-22. https://doi.org/10.1007/s10571-013-0022-9
  25. Barrachina M, Castano E, Dalfo E, Maes T, Buesa C, Ferrer I. Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies. Neurobiol Dis 2006;22:265-73. https://doi.org/10.1016/j.nbd.2005.11.005
  26. Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem 2004;279:13256-64. https://doi.org/10.1074/jbc.M314124200
  27. Lonskaya I, Hebron ML, Desforges NM, Schachter JB, Moussa CE. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med (Berl) 2014;92:373-86. https://doi.org/10.1007/s00109-013-1112-3
  28. Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease. Biochim Biophys Acta BBAMol Basis Dis 2017;1863:1037-45. https://doi.org/10.1016/j.bbadis.2016.04.017
  29. Lu X, Chen H, Dong P, Fu L, Zhang X. Phytochemical characteristics and hypoglycaemic activity of fraction from mushroom Inonotus obliquus. J Sci Food Agric 2010;90:276-80. https://doi.org/10.1002/jsfa.3809
  30. Ma L, Chen H, Dong P, Lu X. Anti-inflammatory and anticancer activities of extracts and compounds from the mushroom Inonotus obliquus. Food Chem 2013;139:503-8. https://doi.org/10.1016/j.foodchem.2013.01.030
  31. Correia SC, Santos RX, Carvalho C, Cardoso S, Candeias E, Santos MS, Oliveira CR, Moreira PI. Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res 2012;1441:64-78. https://doi.org/10.1016/j.brainres.2011.12.063
  32. Paul S. Dysfunction of the ubiquitin-proteasome system in multiple disease conditions: therapeutic approaches. BioEssays 2008;30:1172-84. https://doi.org/10.1002/bies.20852
  33. Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Oddo S. Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice. Aging Cell 2019;18:e12873.
  34. Watanabe T, Hikichi Y, Willuweit A, Shintani Y, Horiguchi T. FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis. J Neurosci 2012;32:3352-65. https://doi.org/10.1523/JNEUROSCI.5659-11.2012
  35. Borgegard T, Gustavsson S, Nilsson C, Parpal S, Klintenberg R, Berg AL, Rosqvist S, Serneels L, Svensson S, Olsson F, et al. Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy. J Neurosci 2012;32:17297-305. https://doi.org/10.1523/JNEUROSCI.1451-12.2012
  36. Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 2006;24:516-24. https://doi.org/10.1016/j.nbd.2006.08.017
  37. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res 2005;2:131-6. https://doi.org/10.2174/1567205053585882
  38. Nalivaeva NN, Turner AJ. Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy. Br J Pharmacol 2019;176:3447-63. https://doi.org/10.1111/bph.14593
  39. Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J, Yeh LA, Cuny GD, Stein RL, Lansbury PT Jr. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. Chem Biol 2003;10:837-46. https://doi.org/10.1016/j.chembiol.2003.08.010
  40. Gentier RJ, van Leeuwen FW. Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease. Front Mol Neurosci 2015;8:47.
  41. Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in Alzheimer's disease. J Neurochem 2000;75:436-9. https://doi.org/10.1046/j.1471-4159.2000.0750436.x
  42. Lopez Salon M, Morelli L, Castano EM, Soto EF, Pasquini JM. Defective ubiquitination of cerebral proteins in Alzheimer's disease. J Neurosci Res 2000;62:302-10. https://doi.org/10.1002/1097-4547(20001015)62:2<302::AID-JNR15>3.0.CO;2-L
  43. Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O. Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 2006;126:775-88. https://doi.org/10.1016/j.cell.2006.06.046
  44. Saido T, Leissring MA. Proteolytic degradation of amyloid β-protein. Cold Spring Harb Perspect Med 2012;2:a006379.
  45. Layfield R, Lowe J, Bedford L. The ubiquitin-proteasome system and neurodegenerative disorders. Essays Biochem 2005;41:157-71. https://doi.org/10.1042/bse0410157
  46. Ross CA, Pickart CM. The ubiquitin-proteasome pathway in Parkinson's disease and other neurodegenerative diseases. Trends Cell Biol 2004;14:703-11. https://doi.org/10.1016/j.tcb.2004.10.006
  47. Uddin MS, Mamun AA, Jakaria M, Thangapandiyan S, Ahmad J, Rahman MA, Mathew B, Abdel-Daim MM, Aleya L. Emerging promise of sulforaphane-mediated Nrf2 signaling cascade against neurological disorders. Sci Total Environ 2020;707:135624.
  48. Upadhya SC, Hegde AN. Ubiquitin-proteasome pathway components as therapeutic targets for CNS maladies. Curr Pharm Des 2005;11:3807-28. https://doi.org/10.2174/138161205774580651
  49. Lonskaya I, Shekoyan AR, Hebron ML, Desforges N, Algarzae NK, Moussa CE. Diminished parkin solubility and co-localization with intraneuronal amyloid-β are associated with autophagic defects in Alzheimer's disease. J Alzheimers Dis 2013;33:231-47. https://doi.org/10.3233/JAD-2012-121141
  50. Khandelwal PJ, Herman AM, Hoe HS, Rebeck GW, Moussa CE. Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Aβ in AD models. Hum Mol Genet 2011;20:2091-102. https://doi.org/10.1093/hmg/ddr091
  51. Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, Martin KC, Kandel ER, Schwartz JH. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 1997;89:115-26. https://doi.org/10.1016/S0092-8674(00)80188-9
  52. Solano RM, Casarejos MJ, Gomez A, Perucho J, de Yebenes JG, Mena MA. Parkin null cortical neuronal/glial cultures are resistant to amyloid-β1-42 toxicity: a role for autophagy? J Alzheimers Dis 2012;32:57-76. https://doi.org/10.3233/JAD-2012-120406
  53. Zhang M, Cai F, Zhang S, Zhang S, Song W. Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo. Sci Rep 2014;4:7298.