Attenuation of beta-amyloid neurotoxicity in vitro by potassium-induced depolarization.
The cell death of cultured neurons triggered by beta-amyloid peptides has been theorized to model, at least in part, the neurodegeneration associated with Alzheimer's disease. To investigate potential strategies to interrupt beta-amyloid neurotoxicity in vitro, we examined the effects of potassium-induced membrane depolarization, a treatment previously demonstrated to reduce development-related apoptosis in cultured neurons. We report here that cultured rat hippocampal neurons pretreated for several hours with 30 mM KCl exhibit significantly reduced vulnerability to aggregated beta-amyloid peptides. The potassium-mediated neuroprotection was mimicked by activation of voltage-sensitive calcium channels using S(-)-Bay K8644 and was attenuated by R(+)-Bay K 8644, a blocker of voltage-dependent calcium channels, and KN-82, an inhibitor of calcium/calmodulin-dependent protein kinase II. The protein synthesis inhibitor cycloheximide also attenuated beta-amyloid neurotoxicity. Addition of cycloheximide following 30 mM KCl significantly increased protection offered by membrane depolarization, whereas cycloheximide addition during membrane depolarization blocked the protective effect. These data suggest that one cellular pathway that can inhibit neuronal death induced by beta-amyloid involves calcium influx through voltage-sensitive channels followed by stimulation of calcium/calmodulin-dependent protein kinase activity and synthesis of new protein(s).
Pike
C J
CJ
Institute for Brain Aging and Dementia, University of California, Irvine 92697-4540, USA.
Balázs
R
R
Cotman
C W
CW
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000473:pathology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D011188:Potassium; D002118:Calcium