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Lipopolysaccharide-Induced Exosomal miR-146a Is Involved in Altered Expression of Alzheimer’s Risk Genes Via Suppression of TLR4 Signaling

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Abstract

Repeated exposure to toll-like receptor 4 (TLR4) ligands, such as lipopolysaccharide (LPS), reduces responses of monocytes/macrophages to LPS (LPS/endotoxin tolerance). Microglial exposure to Aβ deposits, a TLR4 ligand, may cause “Aβ/LPS tolerance,” leading to decreased Aβ clearance. We demonstrated that microglial activation by LPS is diminished in Aβ deposit-bearing 12-month-old model mice of Alzheimer’s disease (AD), compared with non-AD mice and Aβ deposit-free 2-month-old AD mice. Because miR-146a plays a predominant role in inducing TLR tolerance in macrophages and because miR-146a in extracellular vesicles (EVs) shed by inflammatory macrophages increases in circulation, we investigated potential roles of miR-146a and inflammatory EVs in inducing TLR tolerance in microglia and in altering expression of inflammatory AD risk genes. We found that miR-146a upregulation induces TLR tolerance and alters expression of inflammatory AD risk genes in response to LPS treatment in BV2 microglia. LPS brain injection altered expression of the AD risk genes in 12-month-old AD mice but not in non-AD littermates. EVs from inflammatory macrophages polarize BV2 microglia to M1 phenotype and induce TLR tolerance. Microglia exposed to Aβ in the brain show reduced cytokine responses to systemic inflammation due to peripheral LPS injection, indicating TLR/Aβ tolerance in microglia. Our results suggest that increased miR-146a induces microglial Aβ/LPS tolerance and that circulating EVs shed by inflammatory macrophages contribute to microglial Aβ/LPS tolerance, leading to reduced Aβ clearance. Our study also suggests that altered expression of inflammatory AD risk genes may contribute to AD development via the same molecular mechanism underlying LPS tolerance.

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Acknowledgments

We thank Erika Sung for assistance in preparation of this manuscript.

Funding

This research was supported in part by National Institutes of Health grants AG030399, AG042082, AG050854, and AG062179.

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Authors and Affiliations

  1. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, 1 Illini Drive, Peoria, IL, 61605, USA

    Junling Yang, Fiona Malone, Michelle Go, Jinghong Kou, Jeong-Eun Lim & Ken-ichiro Fukuchi

  2. Department of Pathology, University of Illinois College of Medicine Peoria, 1 Illini Drive, Peoria, IL, 61605, USA

    Robert C. Caughey

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  1. Junling Yang
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The research was conducted by Junling Yang, Fiona Malone, Michelle Go, Jinghong Kou, Jeong-Eun Lim, and Robert C. Caughey. The manuscript was written by Junling Yang and Ken-ichiro Fukuchi. The research was conceptualized and designed by Junling Yang and Ken-ichiro Fukuchi.

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Correspondence to Ken-ichiro Fukuchi.

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Yang, J., Malone, F., Go, M. et al. Lipopolysaccharide-Induced Exosomal miR-146a Is Involved in Altered Expression of Alzheimer’s Risk Genes Via Suppression of TLR4 Signaling. J Mol Neurosci 71, 1245–1255 (2021). https://doi.org/10.1007/s12031-020-01750-1

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