Affiliations: [a] Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| [b] Department of Pharmacology and Nutritional Sciences and the Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA
Correspondence:
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Correspondence to: Colin K. Combs, Ph.D. Professor, Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Suite W315, 1301 North Columbia Road Stop 9037, Grand Forks, ND 58202-9037, USA. Tel.: +1 701 777 4025; Fax: +1 701 777 2382; E-mail: colin.combs@med.und.edu.
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 x 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.
