Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models

PLoS One. 2018 May 8;13(5):e0196929. doi: 10.1371/journal.pone.0196929. eCollection 2018.

Abstract

MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Cognitive Dysfunction / genetics
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Humans
  • Infusions, Intraventricular
  • Insulin Receptor Substrate Proteins / genetics*
  • Memory Disorders / genetics
  • Memory Disorders / pathology
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics*
  • Signal Transduction

Substances

  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • MIRN200 microRNA, human
  • MicroRNAs
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse

Grants and funding

This work was supported by the Advanced Research for Products Mining Program [10-43] from the National Institute of Biomedical Innovation of Japan. This work was partially supported by the “Development of Diagnostic Technology for Detection of miRNA in Body Fluids” grant [P14009] from a project commissioned by the New Energy and Industrial Technology Development Organization (NEDO) and from Japan Agency for Medical Research and development (AMED). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.