We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain.
- Authors
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
- 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/ Read the Editorial Highlight for this article on page 8. We hypothesized that calcineurin‐mediated transcriptional changes may contribute to neuropathological changes in Alzheimer's disease because of its involvement in amyloid‐mediated synaptic defects. We tested this hypothesis by examining the impact of constitutively active calcineurin on neuronal gene expression in vivo by intrahippocampal viral transduction followed by laser capture of neuronal cell bodies and microarray analysis of gene expression. We found dramatic transcriptional down‐regulation, especially of synaptic mRNAs, in hippocampal neurons chronically transduced with constitutively active calcineurin. Importantly, the transcriptional profile parallels the changes in human Alzheimer's disease tissue. Additional bioinformatics analyses suggest that both nuclear factor of activated T cells (NFAT) and numerous microRNAs may all be impacted by calcineurin, and parallel findings are observed in Alzheimer's disease. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing Alzheimer's disease may result from aberrant calcineurin activation leading to down‐regulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs. Read the Editorial Highlight for this article on page 8.
- Subjects
CALCINEURIN; ALZHEIMER'S disease; POSTSYNAPTIC potential; AMYLOID plaque; GENE expression; MICRORNA
- Publication
Journal of Neurochemistry, 2018, Vol 147, Issue 1, p24
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.14469