MicroRNA 7 Impairs Insulin Signaling and Regulates Aβ Levels through Posttranscriptional Regulation of the Insulin Receptor Substrate 2, Insulin Receptor, Insulin-Degrading Enzyme, and Liver X Receptor Pathway

ABSTRACT

Brain insulin resistance is a key pathological feature contributing to obesity, diabetes, and neurodegenerative disorders, including Alzheimer’s disease (AD). Besides the classic transcriptional mechanism mediated by hormones, posttranscriptional regulation has recently been shown to regulate a number of signaling pathways that could lead to metabolic diseases. Here, we show that microRNA 7 (miR-7), an abundant microRNA in the brain, targets insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and insulin-degrading enzyme (IDE), key regulators of insulin homeostatic functions in the central nervous system (CNS) and the pathology of AD. In this study, we found that insulin and liver X receptor (LXR) activators promote the expression of the intronic miR-7-1 in vitro and in vivo, along with its host heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene, encoding an RNA binding protein (RBP) that is involved in insulin action at the posttranscriptional level. Our data show that miR-7 expression is altered in the brains of diet-induced obese mice. Moreover, we found that the levels of miR-7 are also elevated in brains of AD patients; this inversely correlates with the expression of its target genes IRS-2 and IDE. Furthermore, overexpression of miR-7 increased the levels of extracellular Aβ in neuronal cells and impaired the clearance of extracellular Aβ by microglial cells. Taken together, these results represent a novel branch of insulin action through the HNRNPK–miR-7 axis and highlight the possible implication of these posttranscriptional regulators in a range of diseases underlying metabolic dysregulation in the brain, from diabetes to Alzheimer’s disease.

KEYWORDS:

• brain insulin resistance
• posttranscriptional RNA binding proteins

ACKNOWLEDGMENTS

This work was supported by grants from the National Institutes of Health (R35HL135820 to C.F.-H.) and the American Heart Association (James and Donna Dickenson-Sublett Award for the Advancement of Cardiovascular Research, SDG23000025, to C.M.R.), the Convocatoria de Atracción de Talento (Modalidad 1) from the Comunidad de Madrid, Spain (reference number 2017T1/BMD5333 to C.M.R.), the Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research MIRVAD (to C.F.-H.), and NIH awards R01AG054102, R01AG053500, R01AG053242, and R21AG050804 (to J.K.), AG028383 (Peter T. Nelson), and NS085830 (Peter T. Nelson).

We thank Peter T. Nelson, who contributed the brain tissues. We thank Santiago Lamas for his help in providing mice and reagents.