Upregulated miRNAs are now generally accepted to predominantly ac

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].

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