Cytochalasins protect hippocampal neurons against amyloid beta-peptide toxicity: evidence that actin depolymerization suppresses Ca2+ influx.
Increasing data suggest that the amyloid beta-peptide (A beta), which accumulates in the brains of Alzheimer's victims, plays a role in promoting neuronal degeneration. Cell culture studies have shown that A beta can be neurotoxic and recent findings suggest that the mechanism involves destabilization of cellular calcium homeostasis. We now report that cytochalasin D, a compound that depolymerizes actin microfilaments selectively, protects cultured rat hippocampal neurons against A beta neurotoxicity. Cytochalasin D was effective at concentrations that depolymerized actin (10-100 nM). The elevation of [Ca2+]i induced by A beta, and the enhancement of [Ca2+]i responses to glutamate in neurons exposed to A beta, were markedly attenuated in neurons pretreated with cytochalasin D. The protective effect of cytochalasin D appeared to result from a specific effect on actin filaments and reduction in calcium influx, because cytochalasin E, another actin filament-disrupting agent, also protected neurons against A beta toxicity; the microtubule-disrupting agent colchicine was ineffective; cytochalasin D did not protect neurons against the toxicity of hydrogen peroxide. These findings suggest that actin filaments play a role in modulating [Ca2+]i responses to neurotoxic insults and that depolymerization of actin can protect neurons against insults relevant to the pathogenesis of Alzheimer's disease.
Furukawa
K
K
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Mattson
M P
MP
D000199:Actins / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003572:Cytochalasins / Q000494:pharmacology*; D004357:Drug Synergism; D004622:Embryo, Mammalian; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D051381:Rats
D000199:Actins; D016229:Amyloid beta-Peptides; D003572:Cytochalasins; D015638:Cytochalasin D; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D002118:Calcium