Apoptosis in Neurons

During development, programmed cell death is a common norm in developing neurons. However, the intrinsic pro-apoptotic pathw ays are obliterated as neurons mature. Thus, mere withdraw al of trophic factors does not suffice in inducing their death. Additionally, a genuine apoptotic signal is required for onset of self-suicide process in neurons. Specific gene-products undertake the apoptotic task in different types of neurons and different stimuli may induce distinct apoptotic pathw ays in them (Pettmann and Henderson, 1998). 

How ever, it is important to acknowledge that apoptosis is not the only means for neurons to die. Death of adult neurons in response to pathological challenges also occurs by necrosis, the unregulated cell death mechanism. Necrosis is mediated by increase in intracellular calcium that catalyses activation of Ca + -dependent cystine proteases like, cathepsins and calpains, w hich primarily compromise lysosomal integrity. Subsequently, these cystine proteases in the company of released lysosomal enzymes dismantle structural netw ork of neuron. Additionally, the intracellular pH also plays a major role in necrosis (Syntichaki and Tavemarakis, 2003). 

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Miura K, Koide N, Himeno S, Nakagawa I, Imura N. 1999. The involvement of microtubular disruption in methyhnercury-induced apoptosis in neuronal and nonneuronal cell lines. Toxicol Appl Pharmacol 160 279-288. 

APP-BPl, first identified as an APP-binding protein, is the regulatory subunit of the activated enzyme for the small ubiquitin-hke protein NEDD8. APP-BPl drives the S- to M-phase transition in dividing cells and causes apoptosis in neurons... 

Chen, Y., McPhie, D.L., Hirschberg, J., Neve, R.L. (2000) The amyloid precursor proteinblinding protein APP-BPl drives the cell cycle through the S-M checkpoint and apoptosis in neurons. J. Biol. Chem., 275, 8929-8935. 

The above examples point out at the direct stimulation of apoptosis by nitric oxide. At the same time, the exclusively rapid reaction of NO with superoxide always suggests the possibility of peroxynitrite participation in this process [141] correspondingly, the role peroxynitrite in the stimulation of apoptosis has been considered. Bonfoco et al. [144] has found that the producers of low peroxynitrite concentrations during the exposure of cortical neurons to the low level of NMDA or the use of peroxynitrite donors resulted in an apoptosis in neurons, while the high concentrations of peroxynitrite induced necrotic cell damage. The formation of peroxynitrite is apparently responsible for NO-stimulated apoptosis in superoxide-generating transformed fibroblasts because nontransformed cells, which do not produce superoxide, were not affected by nitric oxide [145]. It is of interest that proapoptotic effect of peroxynitrite may depend on the cell type. Thus, the formation of peroxynitrite enhanced the NO-induced apoptosis in glomerular endothelial cells, while superoxide inhibited the formation of ceramide and apoptosis in these cells exposed to nitric oxide probably due to peroxynitrite formation... 

Harris CA, Johnson EM Jr (2001), BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons, J. Biol. Chem. 276 37754-37760. 

Caspase-3 Perinatal lethality Excess brain tissue Defective apoptosis in neuronal progenitor cells, forebrain malformation, reduced antigen-induced apoptosis of T cells Normal [61-63]... 

Secreted A]3 and their fragments in various oligomericforms are considered to be, to a different degree, cytotoxic and to induce apoptosis in neuronal cells (131). 

Gorman AM, Orrenius S, Ceccatelli S (1998) Apoptosis in neuronal cells role of caspases. Neuroreport 9 R49-R55... 

Ji, Z.-S., Miranda, R.D., Newhouse, Y.M., Weisgraber, K.H., Huang, Y. and Mahley, R.W. 2002. ApoUpoprotein E4 potentiates amyloid P peptide-induced lysosomal leakage and apoptosis in neuronal cells. J. Biol. Chem. 277 21821-21828 Ji, Z.-S., Mullendorff, K., Cheng, I.-H., Miranda, R.D., Huang, Y and Mahley, R.W. 2006. Reactivity of apolipoprotein E4 and amyloid P peptide Lysosomal stability and neurodegeneration. J. Biol. Chem. 281 2683-2692... 

Recent findings imphcate apoptosis in neuronal degeneration after ischaemic brain injury in animal models of stroke (Mattson et al. 2000). Apoptotic cascades involve increased levels of intraceUular oxyradicals and calcimn induction of expression of proteins such as Par-4 (prostate apoptosis response-4), which act by promoting mitochondrial dysfunction and suppressing antiapoptotic mechanisms mitochondrial membrane depolarisation, calcium uptake, and release of factors (e.g. cytochrome c) that ultimately induce nuclear DNA condensation and fragmentation activation of cysteine proteases of the caspase family activation of transcription factors such as AP-1 that may induce expression of killer genes . 

Heneka, M.T., Loschmann, P.A., Gleichmann, M., Weller, M., Schulz, J.B., Wullner, U., and Klockgether, T. (1998). Induction of nitric oxide synthase and nitric oxide-mediated Apoptosis in neuronal PC 12 cells after stimulation with tumor necrosis factor-alpha/lipopolysaccharide. J. Neurochem. 71, 88-94. 

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