title: 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.
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.
authors.affiliation: Experimental Research Center, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Feng-Li
authors.initials: FL
authors.lastname: Zhao
authors.affiliation: Experimental Research Center, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Experimental Research Center, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Pei-feng
authors.initials: PF
authors.lastname: Qiao
authors.affiliation: Department of Neurology, The University-Town Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yan
authors.affiliation: Experimental Research Center, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Experimental Research Center, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001284:Atrophy; D001921:Brain / Q000187:drug effects / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000378:metabolism*; D013871:Thiones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000610725:AP39 compound; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D053764:Presenilin-1; D013871:Thiones; D006862:Hydrogen Sulfide