Merck
  • Home
  • Search Results
  • Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition.

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

Journal of neuroinflammation (2015-04-19)
Lalida Rojanathammanee, Angela M Floden, Gunjan D Manocha, Colin K Combs
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
チアゾリルブルーテトラゾリウムブロミド, powder, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥97.5% (HPLC)
Sigma-Aldrich
チアゾリルブルーテトラゾリウムブロミド, 98%
Sigma-Aldrich
L-グルタミン, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source
Sigma-Aldrich
HEPES緩衝液, 1 M in H2O
Sigma-Aldrich
フルオロセインイソチオシアナート, アイソマー I, suitable for protein labeling, ≥90% (HPLC), powder
Sigma-Aldrich
L-グルタミン, ReagentPlus®, ≥99% (HPLC)
SAFC
L-グルタミン
SAFC
HEPES
Sigma-Aldrich
HEPES, BioUltra, for molecular biology, ≥99.5% (T)
Sigma-Aldrich
フルオロセイン 5(6)-イソチオシアナート, BioReagent, suitable for fluorescence, mixture of 2 components, ≥90% (HPLC)
Sigma-Aldrich
HEPES, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
SAFC
HEPES
Sigma-Aldrich
L-グルタミン, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
HEPES, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
Sigma-Aldrich
フルオロセインイソチオシアナート, アイソマー I, ≥97.5% (HPLC)
Sigma-Aldrich
L-グルタミン, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
フルオロセイン 5(6)-イソチオシアナート, ≥90% (HPLC)
Sigma-Aldrich
HEPES, anhydrous, free-flowing, Redi-Dri, ≥99.5%
Supelco
L-グルタミン, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
HEPES, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
L-グルタミン
Supelco
L-グルタミン, certified reference material, TraceCERT®
Sigma-Aldrich
HEPES, ≥99.0%
Sigma-Aldrich
L-グルタミン, JIS special grade, ≥99.0%
Sigma-Aldrich
フルオロセインイソチオシアナート, アイソマー I, ≥97.5% (HPLC)