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Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain
Author(s) -
Hopp Sarah C.,
Bihlmeyer Nathan A.,
Corradi John P.,
Vanderburg Charles,
Cacace Angela M.,
Das Sudeshna,
Clark Timothy W.,
Betensky Rebecca A.,
Hyman Bradley T.,
Hudry Eloise
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14469
Subject(s) - calcineurin , neuroscience , neuropathology , biology , transcription factor , gene expression , microbiology and biotechnology , gene , disease , biochemistry , medicine , pathology , transplantation
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.