title: 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.affiliation: College of Pharmacy, Chungbuk National University 48, Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, South Korea.
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Song
authors.forename: Hye Ji
authors.initials: HJ
authors.lastname: Park
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Hwan Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Hee Soon
authors.initials: HS
authors.lastname: Lee
authors.forename: Myung Koo
authors.initials: MK
authors.lastname: Lee
authors.forename: Ki Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Sun-Kyung
authors.initials: SK
authors.lastname: Kang
authors.forename: Seoung Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: 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
chemical_list: 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