Communications Biology (Jan 2021)
Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice
- Andrea Stojakovic,
- Sergey Trushin,
- Anthony Sheu,
- Layla Khalili,
- Su-Youne Chang,
- Xing Li,
- Trace Christensen,
- Jeffrey L. Salisbury,
- Rachel E. Geroux,
- Benjamin Gateno,
- Padraig J. Flannery,
- Mrunal Dehankar,
- Cory C. Funk,
- Jordan Wilkins,
- Anna Stepanova,
- Tara O’Hagan,
- Alexander Galkin,
- Jarred Nesbitt,
- Xiujuan Zhu,
- Utkarsh Tripathi,
- Slobodan Macura,
- Tamar Tchkonia,
- Tamar Pirtskhalava,
- James L. Kirkland,
- Rachel A. Kudgus,
- Renee A. Schoon,
- Joel M. Reid,
- Yu Yamazaki,
- Takahisa Kanekiyo,
- Song Zhang,
- Emirhan Nemutlu,
- Petras Dzeja,
- Adam Jaspersen,
- Ye In Christopher Kwon,
- Michael K. Lee,
- Eugenia Trushina
Affiliations
- Andrea Stojakovic
- Department of Neurology, Mayo Clinic
- Sergey Trushin
- Department of Neurology, Mayo Clinic
- Anthony Sheu
- Institute for Translational Neuroscience, University of Minnesota Twin Cities
- Layla Khalili
- Department of Neurology, Mayo Clinic
- Su-Youne Chang
- Department of Neurologic Surgery, Mayo Clinic
- Xing Li
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic
- Trace Christensen
- Microscopy and Cell Analysis Core, Mayo Clinic
- Jeffrey L. Salisbury
- Microscopy and Cell Analysis Core, Mayo Clinic
- Rachel E. Geroux
- Department of Neurology, Mayo Clinic
- Benjamin Gateno
- Department of Neurology, Mayo Clinic
- Padraig J. Flannery
- Department of Neurology, Mayo Clinic
- Mrunal Dehankar
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic
- Cory C. Funk
- Institute for Systems Biology
- Jordan Wilkins
- Department of Neurology, Mayo Clinic
- Anna Stepanova
- Division of Neonatology, Department of Pediatrics, Columbia University
- Tara O’Hagan
- Division of Neonatology, Department of Pediatrics, Columbia University
- Alexander Galkin
- Division of Neonatology, Department of Pediatrics, Columbia University
- Jarred Nesbitt
- Department of Neurology, Mayo Clinic
- Xiujuan Zhu
- Department of Neurology, Mayo Clinic
- Utkarsh Tripathi
- Department of Neurology, Mayo Clinic
- Slobodan Macura
- Department of Biochemistry and Molecular Biology, Mayo Clinic
- Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic
- Tamar Pirtskhalava
- Robert and Arlene Kogod Center on Aging, Mayo Clinic
- James L. Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic
- Rachel A. Kudgus
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
- Renee A. Schoon
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
- Joel M. Reid
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
- Yu Yamazaki
- Department of Neuroscience, Mayo Clinic
- Takahisa Kanekiyo
- Department of Neuroscience, Mayo Clinic
- Song Zhang
- Department of Cardiovascular Medicine, Mayo Clinic
- Emirhan Nemutlu
- Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Sihhiye
- Petras Dzeja
- Department of Cardiovascular Medicine, Mayo Clinic
- Adam Jaspersen
- Microscopy and Cell Analysis Core, Mayo Clinic
- Ye In Christopher Kwon
- Institute for Translational Neuroscience, University of Minnesota Twin Cities
- Michael K. Lee
- Institute for Translational Neuroscience, University of Minnesota Twin Cities
- Eugenia Trushina
- Department of Neurology, Mayo Clinic
- DOI
- https://doi.org/10.1038/s42003-020-01584-y
- Journal volume & issue
-
Vol. 4,
no. 1
pp. 1 – 20
Abstract
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.
