Okadaic acid induces JNK activation, bim overexpression and mitochondrial dysfunction in cultured rat cortical neurons.
Apoptosis via tau phosphorylation has been implicated in the selective neuronal losses seen in Alzheimer's disease (AD). Previous studies in vivo and in cultured neurons have shown that okadaic acid (OA) evokes tau phosphorylation to initiate a neurodegeneration that resembles the pathogenesis of AD. In an effort to identify additional key molecules in this neurodegeneration, we treated cultured rat neurons with OA and examined the apoptosis-related effects, such as changes in mitochondrial activity and expression levels of JNK, Bim, Bad, Bax and caspase-3. Western blotting revealed that phosphorylation of JNK and c-jun occurred first, followed by increased expression of Bim and subsequent caspase-3 activation in OA-treated neurons. In contrast, Bad levels decreased as early as 4 h after OA treatment. Immunocytochemistry showed that the increased phospho-JNK immunoreactivity was localized in the cytosol of degenerating neurons, while increased phospho-c-jun was localized in the nucleus. The mitochondria showed decreased membrane potential and increased swelling after OA treatment. Collectively, these data suggest that JNK- and Bim-related mitochondrial dysfunction is involved in OA-induced neurodegeneration.
Yoon
SeungYong
S
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 PoongNap-Dong, SongPa-Gu, Seoul 138-736, Korea.
Choi
JungEun
J
Yoon
JuHee
J
Huh
Jae-Wan
JW
Kim
DongHou
D
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019319:Okadaic Acid / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051381:Rats; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051025:bcl-Associated Death Protein / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019319:Okadaic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases