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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.