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 TripathiSlobodan 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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Article number61
JournalCommunications biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
We thank Mayo Clinic Cores for help with FDG-PET; RNA-seq, metabolomics, EM and CLAMS data acquisition; Dr. A. Leontovich, Ms. R. Schlichte, E. Murray, L. G. Andres-Beck, and Mr. I. Trushin for help. This research was supported by grants from the National Institutes of Health NIA RF1AG55549 (to E.T.), NINDS R01NS107265 (to E. T.), RO1AG062135 (to E.T. and M.K.L.), ADDF 291204 (to E.T.), MN Partnership for Biotechnology and Medical Genomics # 15.08 (to E.T. and M.K.L.), NIH RO1NS88260 (to S.Y.C.), NIH RO1 NS112381 (to A.G.), National Cancer Institute Grant P30 CA015083 (to J.M.R.), NIH grants R37AG013925 and P01AG062413 (to J.L.K. and T.T.), the Alzheimer’s Association Part the Cloud Program, Robert and Arlene Kogod, the Connor Group, Robert J. and Theresa W. Ryan, and the Noaber Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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