Differential Regulation of Interleukin-1 Receptor-associated Kinase-1 (IRAK-1) and IRAK-2 by MicroRNA-146a and NF-κB in Stressed Human Astroglial Cells and in Alzheimer Disease

Abstract

The innate immune response and inflammatory signaling play determinant roles in brain homeostasis, neuroprotection, and repair; however, altered or excessive signaling in these injury defense systems contributes to the irreversible degeneration of brain cells, as typified in the common, age-related neurodegenerative disorder Alzheimer disease (AD). Abundant DNA array, Northern, RT-PCR, and Western gene expression analysis of AD brains have repeatedly shown a significant disruption in the homeostatic expression of essential brain genes and a progressive up-regulation of inflammatory gene expression, driven in part by overactivation of transcription factor NF-B. This supports both the development and progression of neurodegenerative disease processes (9 -16). Indeed the TLR/IL-1R-IRAK-NF-B signaling axis is substantially over-stimulated in AD brain (6, 9 -12). Components of this innate immunity and inflammatory pathway are known to play a central role in driving neuropathology, in part via overexpression of interleukin-1 ␤ (IL-1␤) and upregulating the generation of the 42-amino acid amyloid ␤ 42 (A␤42) peptide. These in turn induce transcription from the * This work was supported, in whole or in part, by National Institutes of Health Grant AG18031 (NIA; to W. J. L.

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…Total DNA, RNA, and proteins were isolated from control and AD-affected human brains in primary culture using TRIzol (Invitrogen) as previously described by our laboratory [47][48][49][50][51]; RNA quality was assessed using an Agilent Bioanalyzer 2100 (Lucent Technologies/Caliper Technologies, Palo Alto, CA, USA) and RNA integrity number (RIN) values were typically 8.0-9.0 indicating highquality total RNA [50][51][52][53][54]. Control and AD brain RNA samples were labeled and hybridized and analyzed using GeneChips (Affymetrix, Palo Alto CA, USA) as previously described in detail by our group [49][50][51][52][53][54].…”

Increased IRAK-4 Kinase Activity in Alzheimer’s Disease; IRAK-1/4 Inhibitor I Prevents Pro-inflammatory Cytokine Secretion but not the Uptake of Amyloid Beta by Primary Human Glia

“…Using immunohistochemistry we found significant increased levels of IRAK-4 in brain tissue derived from AD cases compared with control cases. Cui and colleagues previously reported that the levels of IRAK-4 in the superior temporal lobe remained un-altered between control and AD subjects while IRAK-1 levels were decreased in AD [27]. These discrepancies could be explained by the use of different detection techniques.…”

Advances in MicroRNAs and Alzheimer’s Disease Research

“…In control and AD samples a significant up-regulation of miRNA-146a coupled to down-regulation of IRAK-1 and a parallel up-regulation of IRAK-2 was noted. Finally independent regulation of IRAK-1 and IRAK-2 in IL-1+A42 peptide-stressed HAG cells and inducible, NF-kB-sensitive, miRNA-146a-mediated downregulation of IRAK-1 coupled to an NF-kB-induced up-regulation of IRAK-2 expression was demonstrated (Cui et al, 2010). This regulatory network provides an important basis for a self-perpetuating inflammatory signaling loop (Fig.4).…”

“…A mouse and human brain abundant miRNA-146 was upregulated in AD brain and associated with the down-regulation of complement factor H, an important repressor of inflammatory signaling in the complement cascade, in AD brain (Lukiw et al 2008). Furthermore in the hippocampus and neocortex of Alzheimer disease (AD) brain as well as in stressed human astroglial (HAG) cells in primary culture, increased expression of an NF-kB-regulated miRNA-146 down-regulates expression of the interleukin-1 receptor-associated kinase-1 (IRAK-1), an essential component of Toll-like/IL-1 receptor signaling (Cui et al 2010). Family of interleukin-1 receptor-associated kinases (IRAKs) in the human genome, including IRAK-1, IRAK-2, IRAK-4, and IRAK-M, are key mediators in the immune pathways utilized by TLR/IL-1R (TIR) signaling.…”