MicroRNA-135a and -200b, potential Biomarkers for Alzheimer׳s disease, regulate β secretase and amyloid precursor protein

Brain Res. 2014 Oct 2;1583:55-64. doi: 10.1016/j.brainres.2014.04.026. Epub 2014 Aug 22.

Abstract

Amyloid precursor protein (APP) and β-site amyloid precursor protein cleaving enzyme (BACE-1) play important roles in the generation of Alzheimer׳s disease (AD), a progressive neurodegenerative disorder. In the present study, microRNA (miR) microarray was used to analyze the miR expression profiles in the hippocampi from APP/PS1 transgenic and wild type mice. The miRs with significant alteration and putative targets on APP or BACE-1 were retrieved (miR-135a, -200b and -429). The deregulations of these miRs were confirmed in mice and further verified in AD patient samples by qPCR. Primary mouse hippocampal neurons, SH-SY5Y and HEK293 cells were used to study the function of miRs on APP and BACE-1. We found that miR-135a, which was downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, directly interacted with the 3'-UTR of BACE-1 and repressed its expression and activity. On the other hand, miR-200b and -429, which were downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, targeted the 3'-UTR of APP and repressed its expression. Furthermore, Aβ42 could downregulate miR-200b expression which may generate a vicious cycle resulted in accumulating Aβ42. The levels of miR-135a and -200b in the serum of DAT group were significantly lower than that of control groups (P<0.05). The serum miR-200b level of MCI group was higher than that of DAT group (P<0.05) and lower than that of control group (P<0.05). We also found decreased miR-135a and -200b levels in the cerebrospinal fluid of DAT group compared with the control group (P<0.05). In conclusion, these findings showed that miR-135a, -200b and -429 may take part in the progress of AD; miR-200b was of great potential as noninvasive and easily detected blood-based biomarkers of MCI and DAT patients.

Keywords: Alzheimer׳s disease; Amyloid precursor protein; microRNA; β secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Biomarkers / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Cognitive Dysfunction / metabolism
  • Female
  • HEK293 Cells
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism

Substances

  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Biomarkers
  • MIRN135 microRNA, human
  • MIRN200 microRNA, human
  • MIRN429 microRNA, human
  • MIRN429 microRNA, mouse
  • MicroRNAs
  • Mirn135 microRNA, mouse
  • Mirn200 microRNA, mouse
  • PSEN1 protein, human
  • Presenilin-1
  • Amyloid Precursor Protein Secretases