NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or deletion of NFATc2 was sufficient to attenuate the ability of the microglia to secrete cytokines. In order to determine whether the NFATc2 isoform, in particular, was a valid immunomodulatory target in vivo, we crossed an NFATc2−/− line to a well-known AD mouse model, an AβPP/PS1 mouse line. As expected, the AβPP/PS1 × NFATc2−/− mice had attenuated cytokine levels compared to AβPP/PS1 mice as well as reduced microgliosis and astrogliosis with no effect on plaque load. Although some species differences in relative isoform expression may exist between murine and human microglia, it appears that microglial NFAT activity is a viable target for modulating the proinflammatory changes that occur during AD.

Elucidating the Interactive Roles of Glia in Alzheimer's Disease Using Established and Newly Developed Experimental Models

“…When NFATc2 KO mice were crossed with APP/PS1 mice, cytokine levels and microgliosis were reduced. However, there was no effect on plaque load ( 70 ). On the other hand, phagocytic roles of microglial triggering receptor expressed on myeloid cells 2 (TREM2) have been reported in AD and in mice.…”

Ca2+, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases

“…NFAT1 was found at higher levels in astrocyte nuclei in postmortem brain sections taken from human subjects with mild cognitive impairment (Abdul et al, 2009 ). NFAT1 has also been identified in microglia of AD mouse models (Manocha et al, 2017b ). However, relative to all other NFAT isoforms, NFAT4 appears to show the greatest association with astrocytes in intact animals, with comparatively much less expression in neurons (Filosa et al, 2007 ; Serrano-Pérez et al, 2011 ; Neria et al, 2013 ; Caraveo et al, 2014 ; Yan et al, 2014 ; Furman et al, 2016 ; Sompol et al, 2017 ).…”

Safety and Neuroprotective Efficacy of Palm Oil and Tocotrienol-Rich Fraction from Palm Oil: A Systematic Review

“…The brains of patients with Alzheimer's disease demonstrate the presence of fibrillar amyloid-β peptide [55]. In addition, three gene mutations are responsible for Alzheimer's disease, including presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP), with presenilin 1 being the most common [56].…”