Apoptosis in Alzheimer's
Apoptosis is Greek which means, “falling from” or “falling away” and is defined by Wolf and Green (2002) as “a conserved cellular suicide program that eradicates excess or potentially dangerous cells”. This necessary program for suicide in cells can also contribute to the progression of some diseases and disorders. One particular disease in which this has become a salient point is Alzheimer’s disease, amongst a list of other disorders and diseases (Chamond, Anon, Aguilar and Pasadas, 1999).
Detection of cell cycle proteins has been found in human and rat models of Alzheimer’s in several studies (Guo et al., 1998; Gibson, 2001). It has also been substantiated through detection of DNA replication that an ectopic cell cycle is involved which precedes neuronal death (Yang et al., 2001; Herrup et al., 2004) which can lead to apoptosis. The pattern of the cell death itself occurs in such a fashion that it is consistent with apoptosis due to the fact that the cells do not lie together but individually (Siegel et al., 2006).
For apoptotic cell death, one would expect to find apoptotic proteins increased – which is exactly what has been found. Guo et al. showed that the Par-4 (Prostate Apoptosis Response-4) protein expression is increased in neurons that are considered “vulnerable”. Later, Guo et al. (2001) showed that their earlier findings to be substantiated. They found that Par-4 increases the secretion of the amyloid β peptide 42 via a caspase-dependent pathway. It was found that inhibition of caspase activity by a broad spectrum inhibitor weakened the Par-4 induced peptide production. Also, implicated is p53 (Cellular tumor antigen p53) protein which is involved in regulation of the cell cycle, DNA repair and can initiate apoptosis. Ohyagi et al. (2005) found that Aβ 42 activates the p53 promoter subsequently leading to p53 induced apoptosis. All these activities interact within the brain of Alzheimer’s patients – specifically the hippocampus to produce the cognitive deficits we see as a result and “support a role for apoptosis” (Siegel et al., 2006).
References
Chamond, R., Anon, J., Aguilar, C. and Pasadas, F. (1999). Apoptosis and disease. Alergologia e Immunologia Clinica, 14, 367-374.
Gibson, R. (2001). Does apoptosis have a role in neurodegeneration? British Medical Journal, 322, 1539-1540.
Guo, Q., Fu, W., Xie, J., Luo, H., Sells, S., Geddes, J. et al. (1998). Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nature Medicine, 4, 957-962.
Guo, Q., Xie, J., Chang, X. and Du, H. (2001). Prostate apoptosis response-4 enhances secretion of amyloid β peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway. Journal of Biological Chemistry, 276, 16040-16044.
Herrup, K., Neve, R., Ackerman, S. and Copani, A. (2004). Divide and die: Cell cycle events as triggers of nerve cell death. Journal of Neuroscience, 24, 9232-9239.
Ohyagi, Y., Asahara, H., Chui, D., Tsuruta, Y., Sakae, N., Miyoshi, K. et al. (2005). Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB Journal, 19, 255-257.
Siegel, G., Albers, R., Brady, S. and Price, D. (2006). Basic Neurochemistry: Molecular, Cellular and Medical Aspects. (7th ed.). London: Elsevier Academic Press.
Wolf, B. and Green, D. (2002). Apoptosis: Letting slip the dogs of war. Current Biology, 12, R177-R179.
Yang, Y., Geldmacher, D. and Herrup, K. (2001). DNA replication precedes neuronal cell death in Alzheimer’s disease. Journal of Neuroscience, 21, 2661-2668.