alexa Divergent pathways account for two distinct effects of amyloid beta peptides on exocytosis and Ca(2+) currents: involvement of ROS and NF-kappaB.
Medicine

Medicine

Journal of Gerontology & Geriatric Research

Author(s): Green KN, Peers C

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Abstract Amyloid peptides (AbetaPs) are implicated in neuronal death associated with Alzheimer's disease. Their toxicity involves disruption cellular Ca(2+) homeostasis, leading to activation of caspases and cell death. Antioxidants can prevent such cell death and show beneficial clinical effects in Alzheimer's disease patients. Using the model neurosecretory cell line, PC12, we have shown that AbetaPs cause enhancement of evoked exocytosis via formation of a Cd(2+) -resistant Ca(2+) influx pathway, and also cause selective, functional up-regulation of current through L-type Ca(2+) channels. The involvement of reactive oxygen species (ROS) in these effects were investigated by examining the ability of various antioxidants to interfere with these responses. Both melatonin and ascorbic acid fully blocked the enhancement of catecholamine secretion caused by application of AbetaP((1-40)), as monitored in real time amperometrically, but inhibition of the transcriptional regulator NF-kappaB with SN-50 did not affect secretion. Enhanced immunofluorescence, observed in AbetaP-treated cells using a monoclonal antibody raised against the N-terminus of AbetaP, was also suppressed by melatonin. Ascorbic acid, melatonin and ebselen also fully prevented augmentation of whole-cell Ca(2+) currents caused by application of AbetaP((1-40)). By contrast, inhibitors of NF-kappaB (sulfasalazine and SN-50) were able to prevent AbetaP induced Ca(2+) channel current enhancement, whilst inhibitors of mitogen-activated protein kinase and protein kinase C could not. Our results indicate that augmentation or induction by AbetaPs of two important, distinct factors regulating Ca(2+) homeostasis is mediated by increased ROS production, but only one of these (up-regulation of native Ca(2+) channels) requires activation of NF-kappaB.
This article was published in J Neurochem and referenced in Journal of Gerontology & Geriatric Research

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