Protective role of Bcl-2 on beta-amyloid-induced cell death of differentiated PC12 cells: reduction of NF-kappaB and p38 MAP kinase activation.
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.
Song
Youn Sook
YS
College of Pharmacy, Chungbuk National University 48, Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, South Korea.
Park
Hye Ji
HJ
Kim
Soo Yeon
SY
Lee
Seung Ho
SH
Yoo
Hwan Soo
HS
Lee
Hee Soon
HS
Lee
Myung Koo
MK
Oh
Ki Wan
KW
Kang
Sun-Kyung
SK
Lee
Seoung Eun
SE
Hong
Jin Tae
JT
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007211:Indoles; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D020011:Protective Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051381:Rats; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007211:Indoles; D016328:NF-kappa B; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C007293:DAPI; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases