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

Background: Amyloid beta (A beta) peptide is hypothesized to stimulate microglia to acquire their characteristic proinflammatory phenotype in Alzheimer's disease (AD) brains. The specific mechanisms by which A beta 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 A beta-stimulated microgliosis that occurs during disease. Methods: Primary murine microglia cultures were stimulated with A beta in the absence or presence of NFAT inhibitors, FK506 and tat-VIVIT peptide, to quantify secretion of cytokines, neurotoxins, or A beta 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 A beta fibrils in the absence or presence of the NFAT inhibitors, FK506 and tat-VIVIT, to demonstrate that NFAT activity regulated A beta 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 A beta 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 A beta plaque deposition that occur in AD.