Upregulation of Micro RNA-146a (miRNA-146a), A Marker for Inflammatory Neurodegeneration, in Sporadic Creutzfeldt–Jakob Disease (sCJD) and Gerstmann–Straussler–Scheinker (GSS) Syndrome

Abstract

A mouse- and human-brain-abundant, nuclear factor (NF)-кB-regulated, micro RNA-146a (miRNA-146a) is an important modulator of the innate immune response and inflammatory signaling in specific immunological and brain cell types. Levels of miRNA-146a are induced in human brain cells challenged with at least five different species of single- or double-stranded DNA or RNA neurotrophic viruses, suggesting a broad role for miRNA-146a in the brain's innate immune response and antiviral immunity. Upregulated miRNA-146a is also observed in pro-inflammatory cytokine-, Aβ42 peptide- and neurotoxic metal-induced, oxidatively stressed human neuronal-glial primary cell cocultures, in murine scrapie and in Alzheimer's disease (AD) brain. In AD, miRNA-146a levels are found to progressively increase with disease severity and co-localize to brain regions enriched in inflammatory neuropathology. This study provides evidence of upregulation of miRNA-146a in extremely rare (incidence 1–10 per 100 million) human prion-based neurodegenerative disorders, including sporadic Creutzfeldt–Jakob disease (sCJD) and Gerstmann–Straussler–Scheinker syndrome (GSS). The findings suggest that an upregulated miRNA-146a may be integral to innate immune or inflammatory brain cell responses in prion-mediated infections and to progressive and irreversible neurodegeneration of both the murine and human brain.

Acknowledgments

Thanks are extended to the families, physicians, and researchers who contributed to the murine and human brain bank tissue and total RNA resources used in these studies, and especially to Drs. P. Alexandrov, R. I. Carp, L. Carver, C. Chen, S. Gettner, E. Head, H. LeBlanc, W. Poon, T. Saing, and Jian Zhang at donor institutions. Some of the control and pathological brain tissues used in these studies were provided by the Memory Impairments and Neurological Disorders (MIND) Institute at the University of California, Irvine, Alzheimer's Disease Research Center (UCI-ADRC); funding for the UCI-ADRC was provided by NIH/NIA grant P50 AG16573. Thanks are also extended to Drs. Hilary Thompson, Yuan Yuan Li, and Darlene Guillot for expert statistical analysis and technical assistance. These studies were supported in part by a Translational Research Initiative grant from Louisiana State University (WJL), by an Alzheimer Association Investigator-Initiated Research Grant IIRG-09-131729 (WJL), NIH NIA AG18031 (WJL), and by NIH NIA AG038834 (WJL).