Protective role of Bcl-2 on beta-amyloid-induced cell death of differentiated PC12 cells: reduction of NF-kappaB and p38 MAP kinase activation.

Abstract

Activation of the apoptosis program by an increased production of beta-amyloid peptides (Abeta) has been implicated in the neuronal cell death of Alzheimer's disease (AD). Bcl-2 is a well-demonstrated anti-apoptotic protein, however, the mechanisms of anti-apoptotic action of Bcl-2 in Abeta-induced neuronal cell death are not fully understood. In the present study, we therefore have investigated the possibility that overexpression of Bcl-2 may prevent Abeta-induced cell death through inhibition of pro-apoptotic activation of p38 MAP kinase and the transcription factor NF-kappaB in nerve growth factor (NGF)-induced differentiated PC12 cells. Treatment of Abeta into differentiated PC12 cells transfected with plasmid alone resulted in increase of cell death determined by measurement of cytotoxicity and apoptosis in a dose dependent manner. Consistent with the increase of cell death, treatment of Abeta resulted in increase of p38 MAP kinase and NF-kappaB activation. However, overexpression of Bcl-2 reduced Abeta-induced apoptosis, and suppressed the activation of p38 MAP kinase and NF-kappaB. In addition, a p38 MAP kinase specific inhibitor SB 203580 attenuated Abeta-induced apoptosis. This inhibitory effect was correlated well with the inhibition of p38 MAP kniase and NF-kappaB activation. Moreover, inhibition of NF-kappaB activation by sodium salicylates reduced Abeta-induced apoptosis and activation of p38 MAP kinase, and up regulated Bcl-2 expression. These results suggest that Bcl-2 overexpression protects against Abeta-induced cell death of differentiated PC12, and its protective effect may be related to the reduction of Abeta-induced activation of p38 MAP kinase and NF-kappaB.

• Authors: Youn Sook Song, Hye Ji Park, Soo Yeon Kim, Seung Ho Lee, Hwan Soo Yoo, Hee Soon Lee, Myung Koo Lee, Ki Wan Oh, Sun-Kyung Kang, Seoung Eun Lee, Jin Tae Hong
• Journal: Neuroscience research (Neurosci Res) Vol. 49 Issue 1 Pg. 69-80 (May 2004) ISSN: 0168-0102 [Print] Ireland
• PMID: 15099705 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Enzyme Inhibitors
• Indoles
• NF-kappa B
• Protective Agents
• Proto-Oncogene Proteins c-bcl-2
• DAPI
• Nerve Growth Factor
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases

Topics

• Amyloid beta-Peptides (toxicity)
• Animals
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Interactions
• Electrophoretic Mobility Shift Assay (methods)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry (methods)
• Gene Expression Regulation (drug effects)
• Indoles
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• NF-kappa B (metabolism)
• Nerve Growth Factor (pharmacology)
• PC12 Cells
• Protective Agents (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (physiology)
• Rats
• Transfection
• p38 Mitogen-Activated Protein Kinases