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Partial inhibition of mitochondrial complex I ameliorates Alzheimer's disease pathology and cognition in APP/PS1 female mice.
Stojakovic, Andrea; Trushin, Sergey; Sheu, Anthony; Khalili, Layla; Chang, Su-Youne; Li, Xing; Christensen, Trace; Salisbury, Jeffrey L; Geroux, Rachel E; Gateno, Benjamin; Flannery, Padraig J; Dehankar, Mrunal; Funk, Cory C; Wilkins, Jordan; Stepanova, Anna; O'Hagan, Tara; Galkin, Alexander; Nesbitt, Jarred; Zhu, Xiujuan; Tripathi, Utkarsh; Macura, Slobodan; Tchkonia, Tamar; Pirtskhalava, Tamar; Kirkland, James L; Kudgus, Rachel A; Schoon, Renee A; Reid, Joel M; Yamazaki, Yu; Kanekiyo, Takahisa; Zhang, Song; Nemutlu, Emirhan; Dzeja, Petras; Jaspersen, Adam; Kwon, Ye In Christopher; Lee, Michael K; Trushina, Eugenia.
Affiliation
  • Stojakovic A; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Trushin S; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Sheu A; Institute for Translational Neuroscience, University of Minnesota Twin Cities, 2101 6th Street SE, Minneapolis, MN, 55455, USA.
  • Khalili L; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Chang SY; Department of Neurologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Li X; Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Christensen T; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Salisbury JL; Microscopy and Cell Analysis Core, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Geroux RE; Microscopy and Cell Analysis Core, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Gateno B; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Flannery PJ; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Dehankar M; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Funk CC; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Wilkins J; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Stepanova A; Institute for Systems Biology, Seattle, WA, 98109-5263, USA.
  • O'Hagan T; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Galkin A; Division of Neonatology, Department of Pediatrics, Columbia University, 116th St & Broadway, New York, NY, 10027, USA.
  • Nesbitt J; Division of Neonatology, Department of Pediatrics, Columbia University, 116th St & Broadway, New York, NY, 10027, USA.
  • Zhu X; Division of Neonatology, Department of Pediatrics, Columbia University, 116th St & Broadway, New York, NY, 10027, USA.
  • Tripathi U; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Macura S; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Tchkonia T; Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Pirtskhalava T; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Kirkland JL; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Kudgus RA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Schoon RA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Reid JM; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Yamazaki Y; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Kanekiyo T; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Zhang S; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Nemutlu E; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Dzeja P; Department of Cardiovascular Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Jaspersen A; Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Sihhiye, Ankara, 06100, Turkey.
  • Kwon YIC; Department of Cardiovascular Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Lee MK; Microscopy and Cell Analysis Core, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Trushina E; Institute for Translational Neuroscience, University of Minnesota Twin Cities, 2101 6th Street SE, Minneapolis, MN, 55455, USA.
Commun Biol ; 4(1): 61, 2021 01 08.
Article in En | MEDLINE | ID: mdl-33420340
ABSTRACT
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
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Full text: 1 Database: MEDLINE Main subject: Pyrones / Brain / Cognition / Electron Transport Complex I / Alzheimer Disease Language: En Journal: Commun Biol Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Pyrones / Brain / Cognition / Electron Transport Complex I / Alzheimer Disease Language: En Journal: Commun Biol Year: 2021 Type: Article Affiliation country: United States