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Table 1 An NF-κ B-activated miRNA-mediated proinflammatory genetic network in Alzheimer's disease

From: NF-κB-regulated, proinflammatory miRNAs in Alzheimer's disease

Human miRNA mRNA target mRNA function Result of mRNA or gene expression deficit References
miRNA-125b CDKN2A Cyclin-dependent kinase inhibitor 2A cell cycle inhibitor; induces cell cycle arrest Downregulation of cell cycle control: glial cell proliferation [5760]
miRNA-125b SYN-2 Synapsin-2: neuronal synaptic phosphor-protein; coats synaptic vesicles; functions in the regulation of neurotransmitter release Impairment of neurotransmitter release; synaptic signaling deficits [2, 3, 6165]
miRNA-125b 15-LOX-1 ALOX15; arachidonate 15-lipoxygenase; essential in the conversion of docosahexaenoic acid to neuroprotectin D1 (NPD1) Deficit in neurotrophic omega-3 fatty acid derivatives in the brain [3, 6669]
miRNA-146a CFH Complement factor H; repressor of activation of the innate immune response in brain and retina at the C3 to C3b transition; deficits in disease are proinflammatory Defect in control of the innate immune response; chronic stimulation of the innate immune response and proinflammatory signaling [2, 3, 8, 7075]
miRNA-146a IRAK-1 Interleukin-1 receptor-associated kinase 1; initiation of the innate immune response and NF-κB signaling Compensatory surge in IRAK-2 and chronic stimulation of NF-κB signaling in the brain [3, 7679]
miRNA-146a TSPAN12 Transmembrane 4 superfamily member 12; regulator of cell surface receptor signal transduction; activates ADAM10-dependent cleavage activity of βAPP Results in a shift from neurotrophic (sAPPα) to amyloidogenic (Aβ42 peptide) processing of βAPP [3, 8083]
  1. Both miRNA-125b and miRNA-146a target the 3'-UTR of several Alzheimer's disease (AD)-relevant mRNAs; these have been predicted using bioinformatics and confirmed experimentally using multiple analytical approaches including DNA arrays, RT-PCR, Northern and LED-Northern dot blots, and western and ELISA analysis [2, 3, 610, 38, 5157, 78]. Additional and original references are provided here and in the text. Factors that induce NF-κB such as HSV-1 and aluminum also induce the expression of proinflammatory miRNAs such as miRNA-125b and miRNA-146a [73, 83, 86, 88, 101, 102, 106, 107, 110]. Overexpression of just two NF-κB-regulated miRNAs (miRNA-125b and miRNA-146a) may in part explain many of the observed pathogenic features of AD including glial cell proliferation, synaptic signaling and neurotrophic deficits, chronic overstimulation of NF-κB and innate immune signaling and proinflammatory amyloidogenesis [8, 59]. The mRNA targets for miRNA-9, miRNA-34a and miRNA-155 (Figure 1) and other inducible miRNAs, and their possible contribution to alterations in gene expression in AD, are currently under intensive research investigation by multiple research laboratories. ADAM10, a disintegrin and metalloproteinase-10; βAPP, β-amyloid precursor protein; TSPAN12, tetraspanin-12.