Abstract
Purpose :
A characteristic feature of AMD is the accumulation of retinal drusen, yellowish deposits enriched in oxidized proteolipids, complement proteins, serum amyloids and amyloid beta (Aβ) peptides. The abundance of drusen is linked to the inability of homeostatic clearance mechanisms to remove these self-aggregating lesions via a compromised triggering receptor expressed in microglial cells (TREM2)-mediated clearance mechanism, a down-regulation in complement factor H (CFH) and an altered innate-immune signaling system that drives inflammatory neurodegeneration. The purpose of this study was to examine the nature of 2 NF-kB-regulated microRNAs: miRNA-34a and miRNA-146a on TREM2 and CFH signaling in cell cultures, in the retina of amyloid over-expressing transgenic mice and in human AMD retina.
Methods :
anti-miRNA, bioinformatics, cultured microglial cells; mRNA-miRNA arrays; NFkB inhibitors, LED-Northern dot blot, DNA and RNA sequencing, transgenic murine models for AMD (TgAMD)
Results :
miRNA-34a and miRNA-146a are members of a family of inducible, NF-kB-regulated pro-inflammatory miRNAs over-expressed in AMD. Increased miRNA-34a and miRNA-146a abundance leads to decreases in 2 of their messenger RNA (mRNA) targets including those encoding TREM2 and CFH. The inducible down-regulation and insufficiency of TREM2 and CFH appear to be linked to deficits in phagocytosis, amyloidogenesis and innate-immune signaling.
Conclusions :
Our understanding of the highly specialized functions for CNS miRNAs continues to evolve. These data are the first to show: (i) an up-regulated miRNA-34a and miRNA-146a coupled to TREM2 and CFH down-regulation in AMD, a CNS disease associated with drusen formation, Aβ42 accumulation, and defects in the innate-immune response; (ii) that an NF-kB-sensitive miRNA-34a modulation of TREM2 contributes to Aβ42 clearance; (iii) that miRNA-146a modulation of CFH leads to deficiencies in the innate-immune system; (iv) that 4 gene products encoded on 3 different chromosomes (miRNA-34a at chr 1p36.22, TREM2 at chr 6p21.1, miRNA-146a at chr 5q33.3 and CFH at chr 1q31.3) orchestrate a complex Aβ42 clearance and innate-immune system function; (v) that these regulatory systems are inducible from outside of the microglial cell; and (vi) that anti-NF-kB and/or AM-based therapeutic strategies may be useful in the clinical management of AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.