Upregulated miRNAs are now generally accepted to predominantly act to decrease their target mRNA levels, and hence downregulate the genetic information encoded by that target mRNA [41,50-56]. Upregulated miRNAs and downregulated mRNAs may help explain the general downregulation of gene expression as is observed in the AD brain [9,39,42,51,59]. Of the approximately inhibitor Ruxolitinib 2,000 human miRNAs currently known, only about 30 or 40 miRNAs are abundantly expressed in either the brain or the retina [51-56,59]. Figure ?Figure11 describes the expression of a small family of potentially pathogenic, NF-??B-regulated miRNAs that are significantly upregulated by a combinatorial cocktail of [IL-1?? + A??42] in human neuronal-glial (HNG) cells in a primary co-culture [38,55,59].

This represents a physiologically relevant induction as both IL-1?? and A??42 peptides are increased in abundance in AD brain [1-3,12-15,17,18]. The upregulated miRNA results in Figure ?Figure11 have been independently confirmed using RT-PCR and/or Northern and or LED-Northern dot-blot techniques [6,7,55-57,59]. These same miRNAs have been observed to be upregulated in AD and in age-related macular degeneration, but not in unaected anatomical regions of these same brain and retinal tissues [7,8,38,43]. Figure 1 Expression of a small family of potentially pathogenic, NF-??B-regulated miRNAs. (A) Light microscopic photograph of human neuronal-glial (HNG) cells in primary culture stained with: antibody to glial fibrillary acidic protein, a glial-specific …

Common to aged, degenerating brain and retina are significant upregulation of miRNA-125b and miRNA-146a, and their increases positively correlate with AD progression [38,59]. As discussed further below, upregulation of these miRNAs has been shown to be involved with a deficit in synaptic and neurotrophic signaling, synaptogenesis and the induction AV-951 of amyloidogenesis and inflammatory signaling due to their selective targeting of several brain mRNA 3′-UTRs, including a critical down-regulation of 15-lipoxygenase (15-LOX), synapsin-2 (SYN-2), IRAK-1, CFH and tetraspanin-12 (TSPAN12) gene expression [38,55,56,61-82]. Interestingly, the miRNA-mediated downregulation of certain brain mRNAs, and hence the impairment in their expression, contributes downstream to AD-relevant deficits. For example, the miRNA-146a-mediated downregulation of TSPAN12 impairs the disintegrin and metalloproteinase-10 activity, thus shunting ??APP processing activities into more amyloidogenic and proinflammatory A??42-generating not pathways (Table ?(Table1)1) [1-5,80-82].