miR-124 Regulates the Expression of BACE1 in the Hippocampus Under Chronic Cerebral Hypoperfusion

Mol Neurobiol. 2017 May;54(4):2498-2506. doi: 10.1007/s12035-016-9845-y. Epub 2016 Mar 16.


Chronic cerebral hypoperfusion (CCH) is a high-risk factor of Alzheimer's disease (AD). MicroRNAs (miRNAs) are ideal mediators of hypoxic stress responses to facilitate cellular adaptation to long-term hypoxia. MiR-124 is a kind of nervous system-specific miRNAs, and one of its target genes is β-site amyloid precursor protein cleaving enzyme 1 (BACE1). In the present study, miR-124 was found to be inhibited all the time from early to late stage of cerebral hypoxia accompanying with the upregulation of BACE1 protein and overproduction of amyloid-β (Aβ) in the hippocampus from cerebral hypoperfusion rat models. Meanwhile, Aβ could further enhance the expression of BACE1 protein due to the inhibition of miR-124. Thus, miR-124 was the key factor in this hypoxia/Aβ-miR-124-BACE1-Aβ cycle. The activation of EPAC-Rap1 pathway was involved in the inhibition of miR-124 in hippocampus under hypoxia or Aβ insult. Our data suggest that, as an endogenous regulator of BACE1 protein, miR-124 may play a role in AD onset induced by CCH.

Keywords: Alzheimer’s disease; Amyloid-β; Chronic cerebral hypoperfusion; MicroRNA-124; β-Site amyloid precursor protein cleaving enzyme 1.

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / genetics*
  • Aspartic Acid Endopeptidases / metabolism
  • Brain Ischemia / genetics*
  • Brain Ischemia / pathology*
  • Cell Line, Tumor
  • Chronic Disease
  • Down-Regulation / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Hippocampus / pathology*
  • Humans
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Rats, Sprague-Dawley
  • Signal Transduction / genetics
  • Up-Regulation / genetics
  • rap1 GTP-Binding Proteins / metabolism


  • Amyloid beta-Peptides
  • Guanine Nucleotide Exchange Factors
  • MIRN124 microRNA, human
  • MIRN124 microRNA, rat
  • MicroRNAs
  • Rapgef3 protein, rat
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, rat
  • rap1 GTP-Binding Proteins