title: Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia.
abstract: Production of reactive oxygen species (ROS) by microglial cells and subsequent oxidative stress are strongly implicated in the pathogenesis of Alzheimer's disease. Although it is recognized that amyloid-β (Aβ) plays a major role in inducing and regulating microglial ROS production in Alzheimer's disease, to date little is known about cellular mechanisms underlying Aβ-stimulated ROS production. Here, we identified ion channels involved in Aβ-induced microglial ROS production and in Aβ-induced microglial priming. Acute stimulation of microglial cells with either fibrillar Aβ(1-42) (fAβ(1-42) ) or soluble Aβ(1-42) (sAβ(1-42) ) caused significant increases in microglial ROS production, which were abolished by inhibition of TRPV1 cation channels with 5-iodo-resiniferatoxin (I-RTX), but were unaffected by inhibition of K(+) channels with charybdotoxin (CTX). Furthermore, pretreatment with either fAβ(1-42) or sAβ(1-42) induced microglial priming, that is, increased ROS production upon secondary stimulation with the phorbol ester PMA. Microglial priming induced by fAβ(1-42) or sAβ(1-42) remained unaffected by TRPV1 channel inhibition with I-RTX. However, sAβ(1-42) -induced priming was inhibited by CTX and margatoxin, but not by TRAM-34 or paxilline, indicating a role of Kv1.3 voltage-gated K(+) channels, but not of Ca(2+) -activated K(+) channels, in the priming process. In summary, our data suggest that in microglia Aβ-induced ROS production and priming are differentially regulated by ion channels, and that TRPV1 cation channels and Kv1.3 K(+) channels may provide potential therapeutic targets to reduce microglia-induced oxidative stress in Alzheimer's disease.
authors.affiliation: Division of Biomedical Sciences, St. George's University of London, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Schilling
authors.forename: Claudia
authors.initials: C
authors.lastname: Eder
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051664:Kv1.3 Potassium Channel / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D007473:Ion Channels; C496974:Kcna3 protein, mouse; D051664:Kv1.3 Potassium Channel; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C075222:amyloid beta-protein (1-42); D019255:NADPH Oxidases