Regulation of Complement Factor H (CFH) by Multiple miRNAs in Alzheimer’s Disease (AD) Brain

Abstract

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’ 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-κB 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.

Modeling the Dynamic AMD-Associated Chronic Oxidative Stress Changes in Human ESC and iPSC-Derived RPE Cells

“…36,37 Nuclear factor-jB-regulated microRNAs are up-regulated in both AMD and Alzheimer's disease, and certain miRNAs are known to target the 3 0 -UTR of CFH, thereby down-regulating CFH. 10,38 Mir23a has also been found to be decreased in RPE cells from AMD donor eyes and has been associated with cellular resistance to oxidative stress. 26 A reduction in Dicer1 and a concomitant rise in Alu RNA has also been linked to RPE degeneration in AMD.…”

Altered expression of miR-146a in myasthenia gravis

“…miR-146a was upregulated and acted as a biomarker in inflammatory signaling in Prion disease, Alzheimer's disease and status epilepticus. It was believed to be regulated by NF-B and contributed to inflammatory injury [17][18][19][20]. Researches about miR-146a in autoimmune diseases found that compared with healthy subjects, the expression levels of miR-146a in peripheral blood mononuclear cells (PBMC) and the synovial fluid of patients with systemic lupus erythematosus (SLE) were significantly decreased [21].…”

The role of epigenetics in age-related macular degeneration

“…[102][103][104] CFH expression is significantly downregulated in the degenerating brain and retina, suggesting that insufficient quantities of this RCA regulator lead to excessive activation of the innate immune response and proinflammatory signaling. [105][106][107][108][109][110][111][112][113][114][115][116][117] There are many shared pathologic characteristics of Alzheimer's disease (AD) and AMD, including decreases and/or dysfunction in CFH. 118 CFH inhibits alternative pathway activation both in plasma and on cell surfaces by promoting C3b proteolysis.…”