Oxidative stress induced senescence pathway

General description

Oxidative stress is defined as the imbalance between production of reactive oxygen species (ROS) and antioxidant defences. Elevated ROS level can be a result from mitochondrial dysfunction or exposure to interferon-beta (IFNB, IFN-beta)(Moiseeva, Bourdeau, Roux, Deschênes-Simard, & Ferbeyre, 2009)⁠. The downstream of ROS activation are the activation of p38 MAPK and JNKs (MAPK8,9,10). Activated JNK translocates into nucleus where it phosphorylates JUN (Shen et al., 2008; Tamagno et al., 2008)⁠.

ROS can not only induced damage on mitochondrial DNA, lipid, but also trigger chronic inflammation mediated by microglia response to these cellular damages. Therefore, free radical-induced damage to cellular macromolecules and the decline of antioxidant mechanism have been hypothesised to cause ageing and age-related diseases (Finkel & Holbrook, 2000)⁠.

  • Moiseeva, O., Bourdeau, V., Roux, A., Deschênes-Simard, X., & Ferbeyre, G. (2009). Mitochondrial dysfunction contributes to oncogene-induced senescence. Molecular and Cellular Biology, 29, 4495–4507. doi:10.1128/MCB.01868-08
  • Shen, C., Chen, Y., Liu, H., Zhang, K., Zhang, T., Lin, A., & Jing, N. (2008). Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. The Journal of Biological Chemistry, 283, 17721–17730. doi:10.1074/jbc.M800013200
  • Tamagno, E., Guglielmotto, M., Aragno, M., Borghi, R., Autelli, R., Giliberto, L., … Tabaton, M. (2008). Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. Journal of Neurochemistry, 104, 683–695. doi:10.1111/j.1471-4159.2007.05072.x
  • Finkel, T., & Holbrook, N. J. (2000). Oxidants, oxidative stress and the biology of ageing. Nature, 408, 239–247. doi:10.1038/35041687
Reactome REACT_169436.2
Involvement in Alzheimer's disease

Abeta promotes oxidative stress through a NMDAR dependent mechanism (De Felice et al., 2007)⁠. On the other hand, oxidative stress promotes the production of Abeta (Li et al., 2004)⁠ via the elevated expression of beta and gamma secretase by ROS activated JNK  (c-Jun N-terminal kinase) pathway (Shen et al., 2008; Tamagno et al., 2008)⁠.  JNK activation is elevated in AD brain (Lagalwar, Guillozet-Bongaarts, Berry, & Binder, 2006; Zhu et al., 2001)⁠.

Furthermore, in AD patients, homeostasis of several metals (Cu, Zn, and Fe) has shown to be disrupted (Deibel, Ehmann, & Markesbery, 1996; Kenche & Barnham, 2011)⁠, which can result in free-radical production, therefore oxidative stress.

  • De Felice, F. G., Velasco, P. T., Lambert, M. P., Viola, K., Fernandez, S. J., Ferreira, S. T., & Klein, W. L. (2007). Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. The Journal of Biological Chemistry, 282, 11590–11601. doi:10.1074/jbc.M607483200
  • Deibel, M. A., Ehmann, W. D., & Markesbery, W. R. (1996). Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: Possible relation to oxidative stress. Journal of the Neurological Sciences, 143, 137–142. doi:10.1016/S0022-510X(96)00203-1
  • Kenche, V. B., & Barnham, K. J. (2011). Alzheimer’s disease & metals: Therapeutic opportunities. British Journal of Pharmacology. doi:10.1111/j.1476-5381.2011.01221.x
  • Lagalwar, S., Guillozet-Bongaarts, A. L., Berry, R. W., & Binder, L. I. (2006). Formation of phospho-SAPK/JNK granules in the hippocampus is an early event in Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 65, 455–464. doi:10.1097/01.jnen.0000229236.98124.d8
  • Li, F., Calingasan, N. Y., Yu, F., Mauck, W. M., Toidze, M., Almeida, C. G., … Gouras, G. K. (2004). Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. Journal of Neurochemistry, 89, 1308–1312. doi:10.1111/j.1471-4159.2004.02455.x
  • Zhu, X., Raina, A. K., Rottkamp, C. A., Aliev, G., Perry, G., Boux, H., & Smith, M. A. (2001). Activation and redistribution of c-Jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease. Journal of Neurochemistry, 76, 435–441. doi:10.1046/j.1471-4159.2001.00046.x
Proteins involved