AP39, a Mitochondria-Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer's Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons

Oxid Med Cell Longev. 2016;2016:8360738. doi: 10.1155/2016/8360738. Epub 2016 Jan 31.

Abstract

Increasing evidence suggests that mitochondrial functions are altered in AD and play an important role in AD pathogenesis. It has been established that H2S homeostasis is balanced in AD. The emerging mitochondrial roles of H2S include antioxidation, antiapoptosis, and the modulation of cellular bioenergetics. Here, using primary neurons from the well-characterized APP/PS1 transgenic mouse model, we studied the effects of AP39 (a newly synthesized mitochondrially targeted H2S donor) on mitochondrial function. AP39 increased intracellular H2S levels, mainly in mitochondrial regions. AP39 exerted dose-dependent effects on mitochondrial activity in APP/PS1 neurons, including increased cellular bioenergy metabolism and cell viability at low concentrations (25-100 nM) and decreased energy production and cell viability at a high concentration (250 nM). Furthermore, AP39 (100 nM) increased ATP levels, protected mitochondrial DNA, and decreased ROS generation. AP39 regulated mitochondrial dynamics, shifting from fission toward fusion. After 6 weeks, AP39 administration to APP/PS1 mice significantly ameliorated their spatial memory deficits in the Morris water maze and NORT and reduced Aβ deposition in their brains. Additionally, AP39 inhibited brain atrophy in APP/PS1 mice. Based on these results, AP39 was proposed as a promising drug candidate for AD treatment, and its anti-AD mechanism may involve protection against mitochondrial damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / prevention & control*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Atrophy
  • Brain / drug effects
  • Brain / pathology
  • Cytoprotection / drug effects
  • Energy Metabolism* / drug effects
  • Hydrogen Sulfide / metabolism*
  • Magnetic Resonance Imaging
  • Memory Disorders / complications
  • Memory Disorders / drug therapy
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Organophosphorus Compounds / pharmacology
  • Organophosphorus Compounds / therapeutic use*
  • Presenilin-1 / metabolism*
  • Thiones / pharmacology
  • Thiones / therapeutic use*

Substances

  • AP39 compound
  • Amyloid beta-Protein Precursor
  • Neuroprotective Agents
  • Organophosphorus Compounds
  • Presenilin-1
  • Thiones
  • Hydrogen Sulfide