Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia

✍ Scribed by Tom Schilling; Claudia Eder

• Book ID: 102315843
• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 431 KB
• Volume: 226
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.22675

✦ Synopsis

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-b (Ab) plays a major role in inducing and regulating microglial ROS production in Alzheimer's disease, to date little is known about cellular mechanisms underlying Ab-stimulated ROS production. Here, we identified ion channels involved in Ab-induced microglial ROS production and in Ab-induced microglial priming. Acute stimulation of microglial cells with either fibrillar Ab 1-42 (fAb 1-42 ) or soluble Ab 1-42 (sAb 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 þ channels with charybdotoxin (CTX). Furthermore, pretreatment with either fAb 1-42 or sAb 1-42 induced microglial priming, that is, increased ROS production upon secondary stimulation with the phorbol ester PMA. Microglial priming induced by fAb 1-42 or sAb 1-42 remained unaffected by TRPV1 channel inhibition with I-RTX. However, sAb 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 þ channels, but not of Ca 2þ -activated K þ 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 þ channels may provide potential therapeutic targets to reduce microglia-induced oxidative stress in Alzheimer's disease.