Lentivirus-Mediated HDAC3 Inhibition Attenuates Oxidative Stress in APPswe/PS1dE9 Mice

J Alzheimers Dis. 2018;61(4):1411-1424. doi: 10.3233/JAD-170844.

Abstract

Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.

Keywords: Alzheimer’s disease; Hippo signaling pathway; amyloid-β; histone deacetylase 3; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Disease Models, Animal
  • Hippocampus / pathology
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Lentivirus
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism
  • Oxidative Stress*
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / pathology
  • Primary Cell Culture
  • Reactive Oxygen Species / metabolism
  • Spatial Memory
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Reactive Oxygen Species
  • tau Proteins
  • Histone Deacetylases
  • histone deacetylase 3