Figure 3.

Potential pathways to the acquisition of the AD phenotype via multiple miRNA-mRNA interactions; AD brains are associated with non-random increases in the abundance of select pro-inflammatory pathogenic miRNAs including miRNA-34a (dashed arrows) and miRNA-146a (solid arrows); the reason for this selective increase is not well understood but it is known that both miRNA-34a and miRNA-146a are both inducible by the pro-inflammatory transcription factor NF-kB [23–25]; increases in miRNA-34a and miRNA-146a are known to be associated with brain inflammation, changes and/or deficits in the innate-immune system and phagocytosis, tau pathology, synaptic aberrations and deficits in synaptogenesis; via miRNA-mRNA 3′-UTR interactions (Figure 2) up-regulated miRNA-34a and miRNA-146a target strongly down-regulate the expression of SHANK3, a multidomain synapse and scaffolding protein whose deficits are strongly linked to the acquisition of the ‘inflammatory neurodegeneration’ phenotype as exemplified by AD in the brain and age-related macular degeneration (AMD) in the retina; there is a predicted interplay between the down-regulation of SHANK3 gene expression and alterations in inflammation, the innate-immune response and synaptic aberrations which are not well understood; major consequences of up-regulated miRNA-34a and miRNA-146a include (i) the promotion of inflammation and induced changes in the innate-immune signalling [14–20]; and (ii) the down-regulation of the synapse-associated protein SHANK3 and synaptic aberrations leading to synaptic signalling dysfunction as is observed in AD brain [1,24,25].