Amyloid-beta-Induced Reactive Oxygen Species Production and Priming Are Differentially Regulated by Ion Channels in Microglia

作者：Schilling Tom; Eder Claudia^*

来源：Journal of Cellular Physiology, 2011, 226(12): 3295-3302.

DOI：10.1002/jcp.22675

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-beta (A beta) plays a major role in inducing and regulating microglial ROS production in Alzheimer's disease, to date little is known about cellular mechanisms underlying A beta-stimulated ROS production. Here, we identified ion channels involved in A beta-induced microglial ROS production and in A beta-induced microglial priming. Acute stimulation of microglial cells with either fibrillar A beta(1-42) (fA beta(1-42)) or soluble A beta(1-42) (sA beta(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 fA beta(1-42) or sA beta(1-42) induced microglial priming, that is, increased ROS production upon secondary stimulation with the phorbol ester PMA. Microglial priming induced by fA beta(1-42) or sA beta(1-42) remained unaffected by TRPV1 channel inhibition with I-RTX. However, sA beta(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 Ca2+-activated K+ channels, in the priming process. In summary, our data suggest that in microglia Ab-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. J. Cell. Physiol. 226: 3295-3302, 2011.

• 出版日期2011-12