Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer's disease

Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2428-2440. doi: 10.1016/j.bbadis.2019.06.006. Epub 2019 Jun 8.


The purpose of our study is to understand the protective role of miR-455-3p against abnormal amyloid precursor protein (APP) processing, amyloid beta (Aβ) formation, defective mitochondrial biogenesis/dynamics and synaptic damage in AD progression. In-silico analysis of miR-455-3p has identified the APP gene as a putative target. Using mutant APP cells, miR-455-3p construct, biochemical and molecular assays, immunofluorescence and transmission electron microscopy (TEM) analyses, we studied the protective effects of miR-455-3p on - 1) APP regulation, amyloid beta (Aβ)(1-40) & (1-42) levels, mitochondrial biogenesis & dynamics; 3) synaptic activities and 4) cell viability & apoptosis. Our luciferase reporter assay confirmed the binding of miR-455-3p at the 3'UTR of APP gene. Immunoblot, sandwich ELISA and immunostaining analyses revealed that the reduced levels of the mutant APP, Aβ(1-40) & Aβ(1-42), and C99 by miR-455-3p. We also found the reduced levels of mRNA and proteins of mitochondrial biogenesis (PGC1α, NRF1, NRF2, and TFAM) and synaptic genes (synaptophysin and PSD95) in mutant APP cells; on the other hand, mutant APP cells that express miR-455-3p showed increased mRNA and protein levels of biogenesis and synaptic genes. Additionally, expression of mitochondrial fission proteins (DRP1 and FIS1) were decreased while the fusion proteins (OPA1, Mfn1 and Mfn2) were increased by miR-455-3p. Our TEM analysis showed a decrease in mitochondria number and an increase in the size of mitochondrial length in mutant APP cells transfected with miR-455-3p. Based on these observations, we cautiously conclude that miR-455-3p regulate APP processing and protective against mutant APP-induced mitochondrial and synaptic abnormalities in AD.

Keywords: Alzheimer's disease; Amyloid beta; Amyloid precursor protein; Mitochondrial biogenesis; Synaptic proteins; microRNA-455-3p.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Antagomirs / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Humans
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics
  • Mutagenesis
  • Peptide Fragments / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Synapses / metabolism
  • Synaptophysin / genetics
  • Synaptophysin / metabolism


  • 3' Untranslated Regions
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antagomirs
  • MicroRNAs
  • Peptide Fragments
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Synaptophysin
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)