Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain. Issue 1 (7th September 2018) - Hopp, Sarah C.
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 science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found athttps://cos.io/our-services/open-science-badges/ . Read the Editorial Highlight for this article on page 8 . Abstract : 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 . Open Science: This manuscript was awarded with the Open Materials Badge. For more information see:https://cos.io/our-services/open-science-badges/