Apoptotic cleavage of cellular proteins pathway

General description

Apoptosis is the programmed cell death, triggered by a family of cysteine proteases called caspases (Behl, 2000)⁠. Caspases can inactivate vital cellular proteins that protect living cell from apoptosis (e.g. inhibitor of caspase-activated deoxyribonuclease, Bcl-2 family etc..) (Adams & Cory, 1998; Enari et al., 1998)⁠. Caspases can also cleave the proteins that regulate cytoskeleton, therefore alter the structure of the cell (Yin & Stull, 1999)⁠.

References:
  • Adams, J. M., & Cory, S. (1998). The Bcl-2 protein family: arbiters of cell survival. Science, 281, 1322–1326. doi:10.1126/science.281.5381.1322
  • Behl, C. (2000). Apoptosis and Alzheimer’s disease. Journal of Neural Transmission. doi:10.1007/s007020070021
  • Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., & Nagata, S. (1998). A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 391, 43–50. doi:10.1038/34112
  • Yin, H. L., & Stull, J. T. (1999). Proteins that regulate dynamic actin remodeling in response to membrane signaling minireview series. The Journal of Biological Chemistry, 274(46), 32529–30. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10551801
Reactome REACT_107.4
KEGG Pathways 04210
Involvement in Alzheimer's disease

Caspase-3  has been shown to directly cleave APP (Gervais et al., 1999). Caspase-3 mediated APP cleavage also stabilises the Beta-secretase, BACE, which facilitates the production of Abeta (Tesco et al., 2007)⁠.

Caspase not only contributes to the generation of Abeta, it also mediates the toxicity of Abeta, as research show that Abeta exposure induces activation of caspase-3 and apoptosis in cultured cortical neurons⁠ (Marín et al., 2000; Nishimura et al., 2002)⁠.

Finally, caspases provide a link between Abeta and tauopathy, as the activations of caspases result in tau cleavage (Cotman, Poon, Rissman, & Blurton-Jones, 2005)⁠, which leads to tau pathological filaments (Cho & Johnson, 2004; Gamblin et al., 2003)⁠. However, despite the growing number of evidence showing that apoptosis contributes to AD onset and progress in in vitro and transgenic animal model, its direct role in human post-mortem AD brain is still under debate.

References:
  • Cho, J.-H., & Johnson, G. V. W. (2004). Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ. The Journal of Biological Chemistry, 279, 54716–54723. doi:10.1074/jbc.M403364200
  • Cotman, C. W., Poon, W. W., Rissman, R. A., & Blurton-Jones, M. (2005). The role of caspase cleavage of tau in Alzheimer disease neuropathology. Journal of Neuropathology and Experimental Neurology, 64, 104–112.
  • Gamblin, T. C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A. L., … Cryns, V. L. (2003). Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 100, 10032–10037. doi:10.1073/pnas.1630428100
  • Gervais, F. G., Xu, D., Robertson, G. S., Vaillancourt, J. P., Zhu, Y., Huang, J., … Nicholson, D. W. (1999). Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid- beta precursor protein and amyloidogenic Aß peptide formation. Cell, 97, 395–406. doi:10.1016/S0092-8674(00)80748-5
  • Marín, N., Romero, B., Bosch-Morell, F., Llansola, M., Felipo, V., Romá, J., & Romero, F. J. (2000). Beta-Amyloid-induced activation of Caspase-3 in primary cultures of rat neurons. Mechanisms of Ageing and Development, 119, 63–67. doi:10.1016/S0047-6374(00)00172-X
  • Nishimura, I., Uetsuki, T., Kuwako, K., Hara, T., Kawakami, T., Aimoto, S., & Yoshikawa, K. (2002). Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein. Cell Death and Differentiation, 9, 199–208. doi:10.1038/sj/cdd/4400931
  • Tesco, G., Koh, Y. H., Kang, E. L., Cameron, A. N., Das, S., Sena-Esteves, M., … Tanzi, R. E. (2007). Depletion of GGA3 Stabilizes BACE and Enhances ??-Secretase Activity. Neuron, 54, 721–737. doi:10.1016/j.neuron.2007.05.012
Proteins involved
MAPT TAU_HUMAN
AKT1 AKT1_HUMAN
MAPK8 MK08_HUMAN
DSG2 DSG2_HUMAN
Caspase-3 CASP3_HUMAN