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.
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Protein aggregation and neuronal damage result in activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs).
“Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs).”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [29]
Microglia can respond to Aβ or to other danger-associated molecules released by damaged cells by producing reactive oxygen species.
“Microglia can respond to Aβ, or to other danger-associated molecules released by damaged cells, by producing reactive oxygen species (ROS) [16].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [16]
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- Authors
- Schilling, T., & Eder, C.
- Affiliations
- St George's, University of London (GB)
- Corresponding author
- Eder, Claudia
- ORCID
- Schilling, Tom
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2011-09-23
- Volume
- 226
- Issue
- 12
- Pages
- 3295-3302
- ISSN
- 0021-9541 (ISSN-L)
- OpenAlex
- W2047371562
- Cited by
- 117
- References
- 34
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 15 · 2021: 16 · 2020: 5 · 2019: 8 · 2018: 7 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 4 · 2013: 8 · 2012: 6
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- amyloid-beta, reactive oxygen species, microglia, microglial priming, ion channels, TRPV1, Kv1.3 potassium channel, oxidative stress, Alzheimer's disease, fibrillar amyloid-beta, soluble amyloid-beta, charybdotoxin, margatoxin, phorbol ester
- MeSH terms
- Animals, Cell Line, Ion Channels, Peptide Fragments, Amyloid beta-Peptides, Reactive Oxygen Species, Microglia, Oxidative Stress, NADPH Oxidases, Potassium Channel Blockers, TRPV Cation Channels, Mice, Kv1.3 Potassium Channel
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