Receptor-mediated Apoptosis Pathway Research Articles

Lymphocytes with Fas-receptors of readiness to apoptosis in non-psychotic mental disorders

IntroductionApoptosis is a complex physiological process of the organism which supports cellular homeostasis, provides important aspects of development and functioning of the immune system. In various pathological conditions the process of apoptosis can be impaired that leads to decrease or increase in pro-apoptotic activity.Materials and methodsWe conducted investigation of relative and absolute number of CD3+CD95+–lymphocytes in groups of patients with adjustment disorders (n = 90), PTSD (n = 100), organic emotionally labile (asthenic) disorder (n = 232), organic personality disorder (n = 93). Clinical verification was conducted according to ICD–10. Control group included 190 practically healthy persons. Fas protein (CD95) expression on CD3 lymphocytes surfaces was detected using flow cytometry. Cytometric measurements were conducted on flow cytofluorimeter FacsCalibur (Becton Dickinson, US).ResultsIn the control group relative number of CD95+–lymphocytes was 11.6%, absolute–0.21 × 109/L. In all examined patients as compared with control the reliable increase both in relative and absolute number of lymphocytes of CD3+CD95+–phenotype was identified. So, in persons with adjustment disorder content of this indicator made 17.0% and 0.28 × 109/L (Р = 0.0015), in PTSD–18.0% and 0.33 × 109/L (Р = 0.0007) and in patients with organic asthenic disorder–19.0% and 0.32 × 109/L (Р = 0.0048), respectively. The highest content in blood of CD3+–lymphocytes, expressing on the surface of membrane the basic marker of apoptosis CD95 is observed in patients with organic personality disorder: 26.0% and 0.44 × 109/L (Р = 0.0003).ConclusionIn case of intensification of psychopathological symptoms especially in persons with non-psychotic organic mental disorders a receptor-mediated signaling pathway of apoptosis is activated – process of programmed cell death.Disclosure of interestThe authors have not supplied their declaration of competing interest.

A Correlative Study on Aβ and CD95 Pathway Independent to Ca2+Dependent Protease and Activation of Caspase Activation

Amyloid-<TEX>${\beta}$</TEX>-peptide (<TEX>$A{\beta}$</TEX>) is important in the pathogenesis of Alzheimer's disease (AD). Calpain (<TEX>$Ca^{2+}$</TEX>-dependent protease) and caspase-8 (the initiating caspase for the extrinsic, receptor-mediated apoptosis pathway) have been implicated in <TEX>$AD/A{\beta}$</TEX> toxicity. We found that <TEX>$A{\beta}$</TEX> promoted degradation of calpastatin (the specific endogenous calpain inhibitor); calpastatin degradation was prevented by inhibitors of either calpain or caspase-8. The results implied a cross-talk between the two proteases and suggested that one protease was responsible for the activity of the other one. In neuron-like differentiated PC12 cells, calpain promotes active caspase-8 formation from procaspase-8 via the <TEX>$A{\beta}$</TEX> and CD95 pathways, along with degradation of the procaspase-8 processing inhibitor caspase-8 (FLICE)-like inhibitory protein, short isoform (FLIPS). Inhibition of calpain (by pharmacological inhibitors and by overexpression of calpastatin) prevents the cleavage of procaspase-8 to mature, active caspase-8, and inhibits FLIPS degradation in the <TEX>$A{\beta}$</TEX>-treated and CD95-triggered cells. Increased cellular Ca2+ per se results in calpain activation but does not lead to caspase-8 activation or FLIPS degradation. The results suggest that procaspase-8 and FLIPS association with cell membrane receptor complexes is required for calpain-induced caspase-8 activation. The results presented here add to the understanding of the roles of calpain, caspase- 8, and CD95 pathway in <TEX>$AD/A{\beta}$</TEX> toxicity. Calpain-promoted activation of caspase-8 may have implications for other types of CD95-induced cell damage, and for nonapoptotic functions of caspase-8. Inhibition of calpain may be useful for modulating certain caspase-8-dependent processes.

Calpain activates caspase-8 in neuron-like differentiated PC12 cells via the amyloid-β-peptide and CD95 pathways

The neurotoxic amyloid-beta-peptide (Abeta) is important in the pathogenesis of Alzheimer's disease (AD). Calpain (Ca(2+)-dependent protease) and caspase-8 (the initiating caspase for the extrinsic, receptor-mediated apoptosis pathway) have been implicated in AD/Abeta toxicity. We previously found that Abeta promoted degradation of calpastatin (the specific endogenous calpain inhibitor); calpastatin degradation was prevented by inhibitors of either calpain or caspase-8. The results implied a cross-talk between the two proteases and suggested that one protease was responsible for the activity of the other one. We now report on the previously unrecognized caspase-8 activation by calpain. In neuron-like differentiated PC12 cells, calpain promotes active caspase-8 formation from procaspase-8 via the Abeta and CD95 pathways, along with degradation of the procaspase-8 processing inhibitor caspase-8 (FLICE)-like inhibitory protein, short isoform (FLIP(S)). Inhibition of calpain (by pharmacological inhibitors and by overexpression of calpastatin) prevents the cleavage of procaspase-8 to mature, active caspase-8, and inhibits FLIP(S) degradation in the Abeta-treated and CD95-triggered cells. Increased cellular Ca(2+) per se results in calpain activation but does not lead to caspase-8 activation or FLIP(S) degradation. The results suggest that procaspase-8 and FLIP(S) association with cell membrane receptor complexes is required for calpain-induced caspase-8 activation. The results presented here add to the understanding of the roles of calpain, caspase-8, and CD95 pathway in AD/Abeta toxicity. Calpain-promoted activation of caspase-8 may have implications for other types of CD95-induced cell damage, and for nonapoptotic functions of caspase-8. Inhibition of calpain may be useful for modulating certain caspase-8-dependent processes.