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.
Document Type
Article
Publication Date
6-5-2017
Digital Object Identifier (DOI)
https://doi.org/10.3233/JAD-151203
Funding Information
This work was supported by a BrightFocus Foundation grant (A2012115), NIH 1R01AG026330, and NIH 1R01AG042819.
Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/15-1203r1).
Repository Citation
Manocha, Gunjan D.; Ghatak, Atreyi; Puig, Kendra L.; Kraner, Susan D.; Norris, Christopher M.; and Combs, Colin K., "NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer's Disease" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 92.
https://uknowledge.uky.edu/pharmacol_facpub/92
Included in
Diseases Commons, Medical Pharmacology Commons, Pharmacology, Toxicology and Environmental Health Commons
Notes/Citation Information
Published in Journal of Alzheimer's Disease, v. 58, no. 3, p. 775-787.
© 2017 – IOS Press and the authors. All rights reserved
The copyright holders have granted the permission for posting the article here.
The document available for download is the authors' post-peer-review final draft of the article.
The final publication is available at IOS Press through https://doi.org/10.3233/JAD-151203.