Regulation of complement factor H (CFH) by multiple miRNAs in Alzheimer's disease (AD) brain - PubMed (original) (raw)

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Regulation of complement factor H (CFH) by multiple miRNAs in Alzheimer's disease (AD) brain

Walter J Lukiw et al. Mol Neurobiol. 2012 Aug.

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.

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Figures

Fig. 1

Fig. 1

Significantly altered gene expression in Alzheimer’s disease (AD). Palm tree plot utilizing Genespring algorithms (Silicon Genetics Corporation, Redwood City, CA), indicates fold-changes in gene expression versus statistical significance (p, ANOVA) of significantly up- and down-regulated genes in AD versus age-matched controls [4-8]. Non-significant genes (green) indicate genes whose expression in AD versus age-matched controls does not change, such as cycloxygenase-1 (COX-1) and presenilin 1 (PS1). “Outlier” genes showing the most significant down-regulation and up-regulation are sequestered, respectively, to the lowest left- and right-most quadrants of this plot [22, 23]. Significantly up-regulated genes include those encoding the inducible cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2;red) [11-13]; the most significantly down-regulated genes include complement factor H (CFH) [6, 18, 20, 55], synapsin-2 (_SYN_-2) [16, 17], and interleukin-1β associated kinase-1 (IRAK-1; blue) [7, 59]. Other significantly down-regulated genes include the cell-cycle kinase regulator (CDKN2A) [54] and 15-lipoxygenase (15-LOX) [14, 23], omitted here for clarity. _N_=72 age-matched control and AD superior temporal neocortical samples (Brodmann area A22); the control and AD groups each consisted of 14 male and 22 female samples; further details on the pathology of these samples have been recently published [6, 7]

Fig. 2

Fig. 2

Significantly up-regulated miRs in AD versus age-matched controls. In this selective sampling, all control (_N_=5) and AD (_N_=5) neocortical samples were obtained from the superior temporal neocortex (Brodmann area A22) and had post-mortem intervals (PMI; death to brain freezing interval) of 2 h or less [4-8, 11, 12]. Controls were age-matched to moderate cases of AD; further details on the pathology of these samples have been recently published [6, 7]. There were no significant differences in age, PMI, or RNA yield or quality between the two brain groups [6-8]. Of the 12 different Homo sapien micro-RNAs (hsa-miR) shown, miR-146a and miR-125b exhibited the greatest up-regulation compared with age-matched controls (p<0.01, ANOVA); the seventh most up-regulated miR was found to be miR-155 (p<0.05, ANOVA) which can also target the CFH mRNA 3′-UTR (see Fig. 4) [22]. We cannot exclude the participation of other human brain-enriched miRs or sncRNAs which may additionally contribute to the neuropathological mechanisms which define the AD process

Fig. 3

Fig. 3

Effects of interleukin 1-beta (IL-1β) and amyloid beta peptide 42 (Aβ42) on human neuronal-glial (HNG) cell lines in primary culture; effects of NF-kB inhibitors and anti-miRs. inhibition of miR actions using (a) the NF-kB translocation inhibitors pyrollidine dithiocarbamate (PDTC) and the polyphenolic trans-stilbene resveratrol analog CAY10512 (10009536; Cayman Chemical, Ann Arbor, MI) and (b) anti-miRs (AMs, antagomirs) AM-125b and AM-146a. Details of the growth and cytokine IL-1β- and Aβ42-peptide-induced stress of HNG cells have been extensively described by our group [4-8, 12, 14, 20, 22, 23, 27, 32, 37-39]. PDTC and CAY10512 each showed significant reversal of both miR-125b- and miR-146a-induced effects. Qualitatively similar results have been observed in other stressed brain cell types and in Tg2576 and 5xFAD Tg-AD mice [2, 6-8, 22, 55]; _N_= 5; significance over controls; *p<0.05; **p<0.01; a dashed horizontal line at 1.0 indicates baseline (homeostatic) miR-146a (a) and CFH levels (b) in control HNG cells

Fig. 4

Fig. 4

Integrated actions of up-regulated miRs and down-regulated mRNA abundance for AD-relevant gene expression. (a) miR action— convergence: multiple miRs down-regulate a single mRNA target; miR-155 has also been recently implicated in the regulation of CFH expression [22, 40]; miR-146a and miR-155 have overlapping targets in the CFH mRNA 3′-UTR [19]; see also Fig. 2; (b) miR action— divergence: single miRs have multiple mRNA targets. The integrated signaling actions of only a few miRs (miR-125b, miR-146a, and miR-155) can explain many of the pathogenic features of AD including glial cell proliferation (CDKN2A), synaptogenesis (SYN-2), neurotrophism (15-LOX), altered cytokine signaling (IRAK-1; with compensatory IRAK-2 up-regulation) and non-homeostatic activation of innate immunity and inflammatory signaling (CFH) [2, 6, 7, 14, 16, 17, 23, 26, 55]. Interestingly, the expression of miR-125b, miR-146a and miR-155 are under transcriptional regulatory control by the pro-inflammatory transcription factor NF-kB (p50/p65 subunit) [22, 41-46, 56]

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