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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Attenuation of microglial activation in a mouse model of Alzheimer’s disease via NFAT inhibition

Authors: Lalida Rojanathammanee, Angela M Floden, Gunjan D Manocha, Colin K Combs

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Amyloid β (Aβ) peptide is hypothesized to stimulate microglia to acquire their characteristic proinflammatory phenotype in Alzheimer’s disease (AD) brains. The specific mechanisms by which Aβ leads to microglial activation remain an area of interest for identifying attractive molecular targets for intervention. Based upon the fact that microglia express the proinflammatory transcription factor, nuclear factor of activated T cells (NFAT), we hypothesized that NFAT activity is required for the Aβ-stimulated microgliosis that occurs during disease.

Methods

Primary murine microglia cultures were stimulated with Aβ in the absence or presence of NFAT inhibitors, FK506 and tat-VIVIT peptide, to quantify secretion of cytokines, neurotoxins, or Aβ phagocytosis. A transgenic mouse model of AD, APP/PS1, was treated subcutaneously via mini-osmotic pumps with FK506 or tat-VIVIT to quantify effects on cytokines, microgliosis, plaque load, and memory.

Results

Expression of various NFAT isoforms was verified in primary murine microglia through Western blot analysis. Microglial cultures were stimulated with Aβ fibrils in the absence or presence of the NFAT inhibitors, FK506 and tat-VIVIT, to demonstrate that NFAT activity regulated Aβ phagocytosis, neurotoxin secretion, and cytokine secretion. Delivery of FK506 and tat-VIVIT to transgenic APP/PS1 mice attenuated spleen but not brain cytokine levels. However, FK506 and tat-VIVIT significantly attenuated both microgliosis and Aβ plaque load in treated mice compared to controls. Surprisingly, this did not correlate with changes in memory performance via T-maze testing.

Conclusions

Our findings suggest that development of specific NFAT inhibitors may offer promise as an effective strategy for attenuating the microgliosis and Aβ plaque deposition that occur in AD.
Appendix
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Metadata
Title
Attenuation of microglial activation in a mouse model of Alzheimer’s disease via NFAT inhibition
Authors
Lalida Rojanathammanee
Angela M Floden
Gunjan D Manocha
Colin K Combs
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0255-2

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