An NF-κB-sensitive Micro RNA-146a-mediated Inflammatory Circuit in Alzheimer Disease and in Stressed Human Brain Cells

Abstract

Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-B-sensitive miRNA-146a highly complementary to the 3-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1␤, A␤42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-B-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-B inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-Bsensitive miRNA-146a-mediated modulation of CFH gene expression may in part regulate an inflammatory response in AD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.

Neuroprotection of microRNA in neurological disorders (Review)

“…miR-146a is upregulated in human AD brain tissue, and an interaction between miR-146a and complement factor H has been validated, suggesting the possibility that the inhibition of miR-146a leads to a reduction in disease-related inflammation (48). Using the neuropeptide Y (NPY) pre-treated rat cortical neurons of the AD model, miR-30a-5p expression was decreased and brain-derived neurotrophic factor (BDNF) expression was increased at 24 and 48 h, following exposure to Aβ (49).…”

MicroRNAs as a molecular basis for mental retardation, Alzheimer's and prion diseases

“…The fact that miR-146a was found to be upregulated by independent groups, and in both AD (Lukiw et al, 2008) and prion disease (Saba et al, 2008), is noteworthy and adds further to the similarities between these two neurodegenerative diseases. Even when considering and taking into account the relatively short half-lives of some miRNAs (~1 to 3.5 h), short postmortem interval human brain tissues from AD patients exhibited a significant up-regulation of miRNA-146a that was not seen in the same brain regions affected with amyotrophic lateral sclerosis (ALS), schizophrenia or Parkinson's disease (Sethi and Lukiw, 2009), whose pathogenesis is closely related to AD and prion disease in that it involves misfolding and accumulation of fibrillar aggregates of proteins (Tau).…”

“…miR-146a, observed in human AD brains (Lukiw et al, 2008). This miRNA shows a high degree of complementarity to the mRNA 3′UTR of complement factor H (CFH), which is an important repressor of the inflammatory response of the brain.…”

“…Unless a different scenario, in which the upregulation of miR-146a expression itself would represent an etiologic basis common to both AD and prion disease, emerge. In any case, it would be most relevant to expand the list of potential mRNA targets of miR-146a, as initiated with the identification of complement factor H (CFH) by Lukiw et al (2008), in order to get a privileged and novel insight into the pathogenesis of neurodegenerative diseases.…”

The role of epigenetics in age-related macular degeneration

“…[102][103][104] CFH expression is significantly downregulated in the degenerating brain and retina, suggesting that insufficient quantities of this RCA regulator lead to excessive activation of the innate immune response and proinflammatory signaling. [105][106][107][108][109][110][111][112][113][114][115][116][117] There are many shared pathologic characteristics of Alzheimer's disease (AD) and AMD, including decreases and/or dysfunction in CFH. 118 CFH inhibits alternative pathway activation both in plasma and on cell surfaces by promoting C3b proteolysis.…”