Regulation of complement factor H (CFH) by multiple miRNAs in Alzheimer's disease (AD) brain.
Human brain cells rely on a specific subset of microRNAs (miRNAs or miRs) to shape their gene expression patterns, and this is mediated through microRNA effects on messenger RNA (mRNA) speciation and complexity. In recent studies (a) in short post-mortem interval Alzheimer's disease (AD) brain tissues versus age-matched controls, and (b) in pro-inflammatory cytokine- and Aβ42 peptide-stressed human neuronal-glial (HNG) cells in primary culture, we have identified several brain-abundant miRNA species found to be significantly up-regulated, including miR-125b and miR-146a. Both of these nuclear factor kappa B (NF-κB)-activated, 22 nucleotide small non-coding RNAs (sncRNAs) target the mRNA of the key, innate-immune- and inflammation-related regulatory protein, complement factor-H (CFH; chr 1q32), resulting in significant decreases in CFH expression (p < 0.01, ANOVA). Our results further indicate that HNG cells respond to IL-1β + Aβ42-peptide-induced stress by significant NF-κB-modulated up-regulation of miRNA-125b- and miRNA-146a. The complex interactive signaling of NF-κB, miR-125b, miR-146a, and perhaps other miRNAs, further illustrate interplay between inducible transcription factors and multiple pro-inflammatory sncRNAs that regulate CFH expression. The novel concept of miRNA actions involving mRNA target convergence and divergence are proposed and discussed. The combinatorial use of NF-кB inhibitors with anti-miRNAs (AMs; antagomirs) may have potential against CFH-driven pathogenic signaling in neurodegenerative disease, and may redirect our therapeutic perspectives to novel treatment strategies that have not yet been considered.
LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, LA 7011-2272, USA. wlukiw@lsuhsc.edu
Walter J
WJ
Lukiw
Peter N
PN
Alexandrov
D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*
D035683:MicroRNAs; D017242:Complement Factor H