Abstract
MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon© LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM as expected. However, most of the miRNA expression variability that correlated with the presence of early AD-related pathology was seen in GM. We confirm that downregulation of a set of miRNAs in GM (including several miR-15/107 genes and miR-29 paralogs) correlated strongly with the density of diffuse amyloid plaques detected in adjacent tissue. A few miRNAs were differentially expressed in WM, including miR-212 that is downregulated in AD and miR-424 which is upregulated in AD. The expression of certain miRNAs correlates with other miRNAs across different cases, and particular subsets of miRNAs are coordinately expressed in relation to AD-related pathology. These data support the hypothesis that patterns of miRNA expression in cortical GM may contribute to AD pathogenetically, because the aggregate change in miRNA expression observed early in the disease would be predicted to cause profound changes in gene expression.
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Acknowledgments
We are deeply grateful to all of the study participants at the University of Kentucky Alzheimer’s disease Center. We thank Ela Patel, Erin Abner and Sonya Anderson for technical and data support and our clinical colleagues (Drs. Gregory Jicha, Gregory Cooper, and Frederick Schmitt) for their thorough evaluations. This study was supported by Grants R01 NS061933, R21AG036875, and P01 NS058484 from NIH.
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Supplemental Figure 1. Scatterplot shows the extremely high correlation in the results of miRNA profiling performed on the same sample, two months apart.
In this chart, each spot represents a single miRNA (N=430 different miRNAs evaluated corresponding to those miRNAs expressed above background on both microarrays). Note that the R-squared correlation coefficient is over 0.97. (PDF 37 kb)
Supplemental Figure 2. Complete Northern blot data that were performed on 10 different miRNAs with relatively high expression according to the microarrays used in the current studies despite lack of previous evidence of brain expression.
2 μg of RNA were isolated from human frontal cortex (Fr), cerebellum (Cb), hippocampus CA1 (Hi), substantia nigra (SN), and superior and middle temporal gyri (Te), and these samples were run on 15% urea-polyacrylamide gel electrophoresis. Representative ethidium-bromide stained gel is shown at top left. (PDF 107 kb)
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Wang, WX., Huang, Q., Hu, Y. et al. Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 121, 193–205 (2011). https://doi.org/10.1007/s00401-010-0756-0
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DOI: https://doi.org/10.1007/s00401-010-0756-0