Earticle

초록

영어

Amyloid-β-peptide (Aβ) is important in the pathogenesis of Alzheimer’s disease (AD). Calpain (Ca2+ -dependent protease) and caspase-8 (the initiating caspase for the extrinsic, receptor-mediated apoptosis pathway) have been implicated in AD/Aβ toxicity. We found that Aβ 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 Aβ 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 Aβ-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 AD/Aβ 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.

목차

Abstract
 1. Introduction
 2. Experimental Section
  2.1. PC12 Cell Cultures and Differentiation
  2.2. Calpastatin Overexpression in Differentiated PC12 Cells
  2.3. Treatment of Differentiated PC12 Cells withsA∨, Anti-CD95 Antibody, Ca2+, and with Protease Inhibitors
  2.4. Preparation of Cell Extracts for SDS-PAGE, and Immunoblotting Analyses
  2.5. Measurement of Calpain and Caspase Activities in PC12 Cell Extracts
 3. Results and Discussion
  3.1. Activation of Caspase-8 in DifferentiatedPC12 Cells Exposed tosA¡ is Mediated by Calpain
  3.2. Activation and Activity of Calpain andCaspase-8 in Differentiated PC12 Cells Treated with Anti-CD95 Antibody
  3.3. Intracellular Ca2+ Involvement in Calpain andCaspase-8 Activation in αCD95 and sAβ Treated PC12 Cells
  3.4. Increased Cellular Ca2+ per se Leads toCalpain Activation but not to Caspase-8 Activation
  3.5. FLIPS is Degraded in Differentiated PC12Cells Exposed to sAβ and to αCD95, but not When Exposed to High Ca2+
 4. Conclusion
 References

키워드

저자

• Pham Thi Dieu Tuyet [ Department of Biotechnology, Hanoi University of Science and Technology, University of Hanoi, Vietnam. ] Corresponding author

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간행물

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• 간행물명

  통합자연과학논문집(구 조선자연과학논문집) [Journal of Integrative Natural Science]

• 간기

  계간

• pISSN

  2005-1042

• 수록기간

  2008~2026

• 등재여부

  KCI 등재

• 십진분류

  KDC 405 DDC 505