Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer's disease

Eloise Hudry, Hai Yan Wu, Michal Arbel-Ornath, Tadafumi Hashimoto, Roland Matsouaka, Zhanyun Fan, Tara L. Spires-Jones, Rebecca A. Betensky, Brian J. Bacskai, Bradley T. Hyman

Research output: Contribution to journalArticle

Abstract

Amyloid β (Aβ) peptides, the main pathological species associated with Alzheimer's disease (AD), disturb intracellular calcium homeostasis, which in turn activates the calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by Aβ leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without Aβ. Here, we tested the hypothesis that calcineurin mediates neurodegenerative effects via activation of the nuclear transcription factor of activated T-cells (NFAT). We found that both spine loss and dendritic branching simplification induced by Aβ exposure were mimicked by constitutively active NFAT, and abolished when NFAT activation was blocked using the genetically encoded inhibitor VIVIT. When VIVIT was specifically addressed to the nucleus, identical beneficial effects were observed, thus enforcing the role of NFAT transcriptional activity in Aβ-related neurotoxicity. In vivo, when VIVIT or its nuclear counterpart were overexpressed in a transgenic model of Alzheimer's disease via a gene therapy approach, the spine loss and neuritic abnormalities observed in the vicinity of amyloid plaques were blocked. Overall, these results suggest that NFAT/calcineurin transcriptional cascades contribute to Aβ synaptotoxicity, and may provide a new specific set of pathways for neuroprotective strategies.

Original languageEnglish (US)
Pages (from-to)3176-3192
Number of pages17
JournalJournal of Neuroscience
Volume32
Issue number9
DOIs
StatePublished - Feb 29 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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    Hudry, E., Wu, H. Y., Arbel-Ornath, M., Hashimoto, T., Matsouaka, R., Fan, Z., Spires-Jones, T. L., Betensky, R. A., Bacskai, B. J., & Hyman, B. T. (2012). Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer's disease. Journal of Neuroscience, 32(9), 3176-3192. https://doi.org/10.1523/JNEUROSCI.6439-11.2012