Premium
P2‐112: The role of potassium channel Kv1.3 in Aß‐induced microglia activation
Author(s) -
Maezawa Izumi,
Jenkins Paul David,
Sexton Jessica,
Wulff Heike,
Jin LeeWay
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.817
Subject(s) - microglia , neurotoxicity , microbiology and biotechnology , potassium channel , chemistry , patch clamp , blot , membrane potential , hippocampal formation , stimulation , neuroglia , biology , biochemistry , neuroscience , biophysics , inflammation , immunology , central nervous system , receptor , organic chemistry , toxicity , gene
Background:Microglia play a pivotal role in the initiation and progression of Alzheimer’s disease (AD) by either clearing A b deposits through phagocytic activity or by releasing cytotoxic substances in response to activation by various stimuli including Aß aggregates. By mediating membrane potential-activated K + efflux, Kv1.3 channels help maintain a negative membrane potential, which provides the driving force for Ca 2+ entry required for sustained immune cell activation. We study the role and therapeutic significance of microglial Kv1.3 channels in Aß-induced microglial activation. Methods: We treated primary microglial cultures and hippocamopal slices with 10-50 nM Aß oligomers (AßO) to induce microglial activation and determined the expression of Kv1.3 by whole-cell patch clamp, qPCR, Western blotting and immunohistochemistry. In brain, microglial Kv1.3 channels exist in Kv1.3 homotetramers or Kv1.3/Kv1.5 heterotetramers; they are pharmacologically distinct from those in neurons and can be specifically inhibited by our Kv1.3 blocker PAP-1. To test the functional significance of Kv1.3, we therefore determined if co-treatment with PAP-1 inhibited Aß-inducedmicroglial activation and neurotoxicity.We also injected AßO into the hippocampus of rats and determined if intraperitoneally injected PAP-1 could ameliorate hippocampal microglial activation and associated dendritic damage, by immunohistochemistry and Golgi stain. We also tested the ability of PAP-1-treated, cultured microglia to uptake fluorescence-labeled AßO by flow cytometry. Results: Kv1.3 expression was increased in cultured microglia in response to stimulation with AbO. Microglia isolated from the brains of adult 5xFAD mice expressed higher levels of Kv1.3 than microglia isolated from non-transgenic mice. We further observed strong Kv1.3 immunoreactivities in microglia associated with amyloid plaques in brains of 5xFAD mice. PAP-1 inhibited AßO-stimulated nitric oxide production as well as microglia-mediated neurotoxicity in microglial cultures and hippocampal slices. In vivo, administration of PAP-1 blocked Aß-induced microglial activation and preserved dendritic integrity. Kv1.3 blockadewith PAP-1 did not affect phagocytosis of Aß aggregates by microglia, in contrast to doxycyclin.Conclusions:Modulating Kv1.3 activity could “fine-tune” microglial activation to block microglial neurotoxicity and at least partially preserve microglial neuroprotective actions such as Aß clearance. Our results suggest a therapeutic potential of the Kv1.3 blocker PAP-1.