Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain
| Autor: | Rebecca A. Betensky, Bradley T. Hyman, Eloise Hudry, Charles R. Vanderburg, Angela Cacace, John P. Corradi, Nathan A. Bihlmeyer, Timothy Clark, Sudeshna Das, Sarah C. Hopp |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Transcriptional Activation 0301 basic medicine Genetic Vectors Phosphatase Neuropathology Biology Hippocampus Biochemistry Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Alzheimer Disease microRNA Gene expression medicine Animals RNA Messenger Gene Transcription factor Neurons NFATC Transcription Factors Calcineurin Computational Biology medicine.disease Mice Inbred C57BL 030104 developmental biology Gene Expression Regulation Synapses Alzheimer's disease Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neurochemistry. 147:24-39 |
| ISSN: | 0022-3042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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