Regulation of complement factor H (CFH) by multiple miRNAs in Alzheimer's disease (AD) brain
Walter J Lukiw1, Peter N Alexandrov
1LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, LA 7011-2272, USA. wlukiw@lsuhsc.edu
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'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.
Insights
Alzheimer's disease involves specific microRNAs (miRNAs) like miR-125b and miR-146a, which regulate gene expression by targeting complement factor-H (CFH). These miRNAs may offer new therapeutic targets for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are crucial regulators of gene expression in human brain cells.
- Dysregulation of miRNAs is implicated in neurodegenerative diseases like Alzheimer's disease (AD).
- Complement factor-H (CFH) is a key protein involved in innate immunity and inflammation.
Purpose of the Study:
- To investigate the role of specific miRNAs in regulating CFH expression in the context of AD.
- To identify brain-abundant miRNAs that are up-regulated in AD and under inflammatory stress.
- To explore potential therapeutic strategies targeting miRNA-CFH interactions.
Main Methods:
- Analysis of post-mortem Alzheimer's disease brain tissues and age-matched controls.
- In vitro studies using human neuronal-glial (HNG) cells stressed with pro-inflammatory cytokines and Aβ42 peptide.
- Quantification of miRNA and mRNA expression levels.
- Investigation of nuclear factor kappa B (NF-κB) signaling pathways.
Main Results:
- miR-125b and miR-146a were significantly up-regulated in AD brain tissues and stressed HNG cells.
- Both miR-125b and miR-146a target CFH mRNA, leading to decreased CFH expression.
- NF-κB activation modulates the up-regulation of miR-125b and miR-146a in response to stress.
- Evidence suggests complex interplay between NF-κB, miRNAs, and CFH regulation.
Conclusions:
- Specific miRNAs, including miR-125b and miR-146a, play a significant role in regulating CFH expression in the brain.
- These miRNAs are implicated in the inflammatory processes relevant to Alzheimer's disease.
- Combinatorial therapy using NF-κB inhibitors and anti-miRNAs (AMs) shows potential for treating neurodegenerative diseases by targeting CFH-driven pathways.
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