Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Ca2+-Permeable TRPV1 Receptor Mediates Neuroprotective Effects in a Mouse Model of Alzheimer's Disease via BDNF/CREB Signaling Pathway

  • Juyong Kim (Department of Agricultural Biotechnology, Seoul National University) ;
  • Sangwoo Seo (Department of Agricultural Biotechnology, Seoul National University) ;
  • Jung Han Yoon Park (Bio-MAX Institute, Seoul National University) ;
  • Ki Won Lee (Department of Agricultural Biotechnology, Seoul National University) ;
  • Jiyoung Kim (Center for Food and Bioconvergence, College of Agriculture and Life Sciences, Seoul National University) ;
  • Jin-Chul Kim (Natural Product Research Center, Korea Institute of Science and Technology (KIST))
  • Received : 2022.10.12
  • Accepted : 2023.01.06
  • Published : 2023.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

Transient receptor potential vanilloid 1 (TRPV1) protein is a Ca2+-permeable non-selective cation channel known for its pain modulation pathway. In a previous study, it was discovered that a triple-transgenic Alzheimer's disease (AD) mouse model (3xTg-AD+/+) has anti-AD effects. The expression of proteins in the brain-derived neurotrophic factor (BDNF)/cAMP response element binding protein (CREB) pathway in a 3xTg-AD/TRPV1 transgenic mice model was investigated to better understand the AD regulatory effect of TRPV1 deficiency. The results show that TRPV1 deficiency leads to CREB activation by increasing BDNF levels and promoting phosphorylation of tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and CREB in the hippocampus. Additionally, TRPV1 deficiency-induced CREB activation increases the antiapoptotic factor B-cell lymphoma 2 (Bcl-2) gene, which consequently downregulates Bcl-2-associated X (Bax) expression and decreases cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), which leads to the prevention of hippocampal apoptosis. In conclusion, TRPV1 deficiency exhibits neuroprotective effects by preventing apoptosis through the BDNF/CREB signal transduction pathway in the hippocampus of 3xTg-AD mice.

Keywords

Acknowledgement

This research was supported by intramural grants (2E31881) from the Korea Institute of Science and Technology (KIST) and the Basic Science Research Program (2018R1D1A1B07050182) from the Ministry of Education in Korea.

References

  1. Antonsson, B., Conti, F., Ciavatta, A., Montessuit, S., Lewis, S., Martinou, I., Bernasconi, L., Bernard, A., Mermod, J.J., Mazzei, G., et al. (1997). Inhibition of Bax channel-forming activity by Bcl-2. Science 277, 370-372. https://doi.org/10.1126/science.277.5324.370
  2. Asadi, M., Taghizadeh, S., Kaviani, E., Vakili, O., Taheri-Anganeh, M., Tahamtan, M., and Savardashtaki, A. (2022). Caspase-3: structure, function, and biotechnological aspects. Biotechnol. Appl. Biochem. 69, 1633-1645. https://doi.org/10.1002/bab.2233
  3. Baker, K.D., Edwards, T.M., and Rickard, N.S. (2013). The role of intracellular calcium stores in synaptic plasticity and memory consolidation. Neurosci. Biobehav. Rev. 37, 1211-1239. https://doi.org/10.1016/j.neubiorev.2013.04.011
  4. Berridge, M.J. (2011). Calcium signalling and Alzheimer's disease. Neurochem. Res. 36, 1149-1156. https://doi.org/10.1007/s11064-010-0371-4
  5. Bloom, G.S. (2014). Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505-508. https://doi.org/10.1001/jamaneurol.2013.5847
  6. Bojarski, L., Herms, J., and Kuznicki, J. (2008). Calcium dysregulation in Alzheimer's disease. Neurochem. Int. 52, 621-633. https://doi.org/10.1016/j.neuint.2007.10.002
  7. Calissano, P., Matrone, C., and Amadoro, G. (2009). Apoptosis and in vitro Alzheimer's disease neuronal models. Commun. Integr. Biol. 2, 163-169. https://doi.org/10.4161/cib.7704
  8. Calvo-Rodriguez, M., Hou, S.S., Snyder, A.C., Kharitonova, E.K., Russ, A.N., Das, S., Fan, Z., Muzikansky, A., Garcia-Alloza, M., Serrano-Pozo, A., et al. (2020). Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease. Nat. Commun. 11, 2146.
  9. Cascella, R. and Cecchi, C. (2021). Calcium dyshomeostasis in Alzheimer's disease pathogenesis. Int. J. Mol. Sci. 22, 4914.
  10. Corona, C., Masciopinto, F., Silvestri, E., Viscovo, A.D., Lattanzio, R., Sorda, R.L., Ciavardelli, D., Goglia, F., Piantelli, M., Canzoniero, L.M., et al. (2010). Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction. Cell Death Dis. 1, e91.
  11. Cregan, S.P., MacLaurin, J.G., Craig, C.G., Robertson, G.S., Nicholson, D.W., Park, D.S., and Slack, R.S. (1999). Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J. Neurosci. 19, 7860-7869. https://doi.org/10.1523/JNEUROSCI.19-18-07860.1999
  12. D'Amelio, M., Sheng, M., and Cecconi, F. (2012). Caspase-3 in the central nervous system: beyond apoptosis. Trends Neurosci. 35, 700-709. https://doi.org/10.1016/j.tins.2012.06.004
  13. DeTure, M.A. and Dickson, D.W. (2019). The neuropathological diagnosis of Alzheimer's disease. Mol. Neurodegener. 14, 32.
  14. Du, Y., Fu, M., Huang, Z., Tian, X., Li, J., Pang, Y., Song, W., Tian Wang, Y., and Dong, Z. (2020). TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease. Aging Cell 19, e13113.
  15. Eimer, W.A. and Vassar, R. (2013). Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation. Mol. Neurodegener. 8, 2.
  16. Elena-Real, C.A., Diaz-Quintana, A., Gonzalez-Arzola, K., Velazquez-Campoy, A., Orzaez, M., Lopez-Rivas, A., Gil-Caballero, S., De la Rosa, M.A., and Diaz-Moreno, I. (2018). Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition. Cell Death Dis. 9, 365.
  17. Ferrer, I., Marin, C., Rey, M.J., Ribalta, T., Goutan, E., Blanco, R., Tolosa, E., and Marti, E. (1999). BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. J. Neuropathol. Exp. Neurol. 58, 729-739. https://doi.org/10.1097/00005072-199907000-00007
  18. Finkbeiner, S., Tavazoie, S.F., Maloratsky, A., Jacobs, K.M., Harris, K.M., and Greenberg, M.E. (1997). CREB: a major mediator of neuronal neurotrophin responses. Neuron 19, 1031-1047. https://doi.org/10.1016/S0896-6273(00)80395-5
  19. Fletcher, J.I., Meusburger, S., Hawkins, C.J., Riglar, D.T., Lee, E.F., Fairlie, W.D., Huang, D.C., and Adams, J.M. (2008). Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax. Proc. Natl. Acad. Sci. U. S. A. 105, 18081-18087. https://doi.org/10.1073/pnas.0808691105
  20. Folch, J., Busquets, O., Ettcheto, M., Sanchez-Lopez, E., Castro-Torres, R.D., Verdaguer, E., Garcia, M.L., Olloquequi, J., Casadesus, G., Beas-Zarate, C., et al. (2018). Memantine for the treatment of dementia: a review on its current and future applications. J. Alzheimers Dis. 62, 1223-1240. https://doi.org/10.3233/JAD-170672
  21. Fumagalli, F., Racagni, G., and Riva, M. (2006). The expanding role of BDNF: a therapeutic target for Alzheimer's disease? Pharmacogenomics J. 6, 8-15. https://doi.org/10.1038/sj.tpj.6500337
  22. Gorman, A.M., Ceccatelli, S., and Orrenius, S. (2000). Role of mitochondria in neuronal apoptosis. Dev. Neurosci. 22, 348-358. https://doi.org/10.1159/000017460
  23. Green, K.N. and LaFerla, F.M. (2008). Linking calcium to Abeta and Alzheimer's disease. Neuron 59, 190-194. https://doi.org/10.1016/j.neuron.2008.07.013
  24. Hippius, H. and Neundorfer, G. (2003). The discovery of Alzheimer's disease. Dialogues Clin. Neurosci. 5, 101-108. https://doi.org/10.31887/DCNS.2003.5.1/hhippius
  25. Ichimiya, Y., Emson, P.C., Mountjoy, C.Q., Lawson, D.E.M., and Heizmann, C.W. (1988). Loss of calbindin-28K immunoreactive neurones from the cortex in Alzheimer-type dementia. Brain Res. 475, 156-159. https://doi.org/10.1016/0006-8993(88)90210-7
  26. Impey, S., Obrietan, K., and Storm, D.R. (1999). Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23, 11-14. https://doi.org/10.1016/S0896-6273(00)80747-3
  27. Jadiya, P., Kolmetzky, D.W., Tomar, D., Di Meco, A., Lombardi, A.A., Lambert, J.P., Luongo, T.S., Ludtmann, M.H., Pratico, D., and Elrod, J.W. (2019). Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer's disease. Nat. Commun. 10, 3885.
  28. Jantas, D., Szymanska, M., Budziszewska, B., and Lason, W. (2009). An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons. Apoptosis 14, 900-912. https://doi.org/10.1007/s10495-009-0370-6
  29. Kim, J., Lee, S., Kim, J., Ham, S., Park, J.H.Y., Han, S., Jung, Y.K., Shim, I., Han, J.S., Lee, K.W., et al. (2020). Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer's disease. Hum. Mol. Genet. 29, 228-237. https://doi.org/10.1093/hmg/ddz276
  30. Ku, B., Liang, C., Jung, J.U., and Oh, B.H. (2011). Evidence that inhibition of BAX activation by BCL-2 involves its tight and preferential interaction with the BH3 domain of BAX. Cell Res. 21, 627-641. https://doi.org/10.1038/cr.2010.149
  31. LeBlanc, A.C. (2005). The role of apoptotic pathways in Alzheimer's disease neurodegeneration and cell death. Curr. Alzheimer Res. 2, 389-402. https://doi.org/10.2174/156720505774330573
  32. Lee, J., Saloman, J.L., Weiland, G., Auh, Q.S., Chung, M.K., and Ro, J.Y. (2012). Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle. Pain 153, 1514-1524. https://doi.org/10.1016/j.pain.2012.04.015
  33. Lu, J., Zhou, W., Dou, F., Wang, C., and Yu, Z. (2021). TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease. EMBO Rep. 22, e52013.
  34. Meller, R., Minami, M., Cameron, J.A., Impey, S., Chen, D., Lan, J.Q., Henshall, D.C., and Simon, R.P. (2005). CREB-mediated Bcl-2 protein expression after ischemic preconditioning. J. Cereb. Blood Flow Metab. 25, 234-246. https://doi.org/10.1038/sj.jcbfm.9600024
  35. Minichiello, L., Calella, A.M., Medina, D.L., Bonhoeffer, T., Klein, R., and Korte, M. (2002). Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36, 121-137. https://doi.org/10.1016/S0896-6273(02)00942-X
  36. Miranda, M., Morici, J.F., Zanoni, M.B., and Bekinschtein, P. (2019). Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front. Cell. Neurosci. 13, 363.
  37. Park, E.M. and Cho, S. (2006). Enhanced ERK dependent CREB activation reduces apoptosis in staurosporine-treated human neuroblastoma SK-N-BE (2) C cells. Neurosci. Lett. 402, 190-194. https://doi.org/10.1016/j.neulet.2006.04.004
  38. Porter, A.G. and Janicke, R.U. (1999). Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6, 99-104. https://doi.org/10.1038/sj.cdd.4400476
  39. Rai, S.N., Dilnashin, H., Birla, H., Singh, S.S., Zahra, W., Rathore, A.S., Singh, B.K., and Singh, S.P. (2019). The role of PI3K/Akt and ERK in neurodegenerative disorders. Neurotox. Res. 35, 775-795. https://doi.org/10.1007/s12640-019-0003-y
  40. Robinson, D.M. and Keating, G.M. (2006). Memantine: a review of its use in Alzheimer's disease. Drugs 66, 1515-1534. https://doi.org/10.2165/00003495-200666110-00015
  41. Sairanen, T., Szepesi, R., Karjalainen-Lindsberg, M.L., Saksi, J., Paetau, A., and Lindsberg, P.J. (2009). Neuronal caspase-3 and PARP-1 correlate differentially with apoptosis and necrosis in ischemic human stroke. Acta Neuropathol. 118, 541-552. https://doi.org/10.1007/s00401-009-0559-3
  42. Santos, A.R., Comprido, D., and Duarte, C.B. (2010). Regulation of local translation at the synapse by BDNF. Prog. Neurobiol. 92, 505-516. https://doi.org/10.1016/j.pneurobio.2010.08.004
  43. Saura, C.A. and Valero, J. (2011). The role of CREB signaling in Alzheimer's disease and other cognitive disorders. Rev. Neurosci. 22, 153-169. https://doi.org/10.1515/rns.2011.018
  44. Scheff, S.W. and Price, D.A. (2006). Alzheimer's disease-related alterations in synaptic density: neocortex and hippocampus. J. Alzheimers Dis. 9(3 Suppl), 101-115. https://doi.org/10.3233/JAD-2006-9S312
  45. Shacka, J.J. and Roth, K.A. (2005). Regulation of neuronal cell death and neurodegeneration by members of the Bcl-2 family: therapeutic implications. Curr. Drug Targets CNS Neurol. Disord. 4, 25-39. https://doi.org/10.2174/1568007053005127
  46. Takahashi, K., Nakagawasai, O., Nemoto, W., Kadota, S., Isono, J., Odaira, T., Sakuma, W., Arai, Y., Tadano, T., and Tan-No, K. (2018). Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice. Neuropharmacology 137, 141-155. https://doi.org/10.1016/j.neuropharm.2018.04.013
  47. Tanqueiro, S.R., Ramalho, R.M., Rodrigues, T.M., Lopes, L.V., Sebastiao, A.M., and Diogenes, M.J. (2018). Inhibition of NMDA receptors prevents the loss of BDNF function induced by amyloid β. Front. Pharmacol. 9, 237.
  48. Vanhoutte, P. and Bading, H. (2003). Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation. Curr. Opin. Neurobiol. 13, 366-371. https://doi.org/10.1016/S0959-4388(03)00073-4
  49. Wang, X. (2001). The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922-2933.
  50. Wang, X., Chen, J., Wang, H., Yu, H., Wang, C., You, J., Wang, P., Feng, C., Xu, G., Wu, X., et al. (2017a). Memantine can reduce ethanol-induced caspase-3 activity and apoptosis in H4 cells by decreasing intracellular calcium. J. Mol. Neurosci. 62, 402-411. https://doi.org/10.1007/s12031-017-0948-3
  51. Wang, X., Yu, H., You, J., Wang, C., Feng, C., Liu, Z., Li, Y., Wei, R., Xu, S., Zhao, R., et al. (2018). Memantine can improve chronic ethanol exposure-induced spatial memory impairment in male C57BL/6 mice by reducing hippocampal apoptosis. Toxicology 406-407, 21-32. https://doi.org/10.1016/j.tox.2018.05.013
  52. Wang, Y., Shi, Y., and Wei, H. (2017b). Calcium dysregulation in Alzheimer's disease: a target for new drug development. J. Alzheimers Dis. Parkinsonism 7, 374.
  53. Yin, X.M., Oltvai, Z.N., and Korsmeyer, S.J. (1994). BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369, 321-323. https://doi.org/10.1038/369321a0
  54. Yuan, J., Murrell, G.A., Trickett, A., and Wang, M.X. (2003). Involvement of cytochrome c release and caspase-3 activation in the oxidative stress-induced apoptosis in human tendon fibroblasts. Biochim. Biophys. Acta 1641, 35-41. https://doi.org/10.1016/S0167-4889(03)00047-8
  55. Zarneshan, S.N., Fakhri, S., and Khan, H. (2022). Targeting Akt/CREB/BDNF signaling pathway by ginsenosides in neurodegenerative diseases: a mechanistic approach. Pharmacol. Res. 177, 106099.
  56. Zhai, K., Liskova, A., Kubatka, P., and Busselberg, D. (2020). Calcium entry through TRPV1: a potential target for the regulation of proliferation and apoptosis in cancerous and healthy cells. Int. J. Mol. Sci. 21, 4177.
  57. Zheng, Z., Sabirzhanov, B., and Keifer, J. (2010). Oligomeric amyloid-β inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning. J. Biol. Chem. 285, 34708-34717. https://doi.org/10.1074/jbc.M110.150821
  58. Zhu, G., Li, J., He, L., Wang, X., and Hong, X. (2015). MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway. Br. J. Pharmacol. 172, 2354-2368. https://doi.org/10.1111/bph.13061