Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain

Sarah C. Hopp, Nathan A. Bihlmeyer, John P. Corradi, Charles Vanderburg, Angela M. Cacace, Sudeshna Das, Timothy W. Clark, Rebecca A. Betensky, Bradley T. Hyman, Eloise Hudry

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Synaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid-β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid-β synaptotoxicity. We therefore hypothesized that CN-mediated transcriptional changes may contribute to AD neuropathology and tested this by examining the impact of CN over-expression on neuronal gene expression in vivo. We found dramatic transcriptional down-regulation, especially of synaptic mRNAs, in neurons chronically exposed to CN activation. Importantly, the transcriptional profile parallels the changes in human AD tissue. Bioinformatics analyses suggest that both nuclear factor of activated T cells and numerous microRNAs may all be impacted by CN, and parallel findings are observed in AD. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing AD may result from aberrant CN activation leading to down-regulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs. Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/. (Figure presented.). Read the Editorial Highlight for this article on page 8.

Original languageEnglish (US)
Pages (from-to)24-39
Number of pages16
JournalJournal of neurochemistry
Volume147
Issue number1
DOIs
StatePublished - Oct 2018

Keywords

  • Alzheimer's disease
  • calcineurin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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