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

doi:10.1038/s42003-020-01584-y

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

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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 language	English (US)
Article number	61
Journal	Communications biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-01584-y
State	Published - 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.

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© 2021, The Author(s).

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Stojakovic, A., Trushin, S., Sheu, A., Khalili, L., Chang, S. Y., Li, X., Christensen, T., Salisbury, J. L., Geroux, R. E., Gateno, B., Flannery, P. J., Dehankar, M., Funk, C. C., Wilkins, J., Stepanova, A., O’Hagan, T., Galkin, A., Nesbitt, J., Zhu, X., ... Trushina, E. (2021). Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice. Communications biology, 4(1), Article 61. https://doi.org/10.1038/s42003-020-01584-y

Stojakovic, A, Trushin, S, Sheu, A, Khalili, L, Chang, SY, Li, X, Christensen, T, Salisbury, JL, Geroux, RE, Gateno, B, Flannery, PJ, Dehankar, M, Funk, CC, Wilkins, J, Stepanova, A, O’Hagan, T, Galkin, A, Nesbitt, J, Zhu, X, Tripathi, U, Macura, S, Tchkonia, T, Pirtskhalava, T, Kirkland, JL, Kudgus, RA, Schoon, RA, Reid, JM, Yamazaki, Y, Kanekiyo, T, Zhang, S, Nemutlu, E, Dzeja, P, Jaspersen, A, Kwon, YIC, Lee, MK & Trushina, E 2021, 'Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice', Communications biology, vol. 4, no. 1, 61. https://doi.org/10.1038/s42003-020-01584-y

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title = "Partial inhibition of mitochondrial complex I ameliorates Alzheimer{\textquoteright}s disease pathology and cognition in APP/PS1 female mice",

abstract = "Alzheimer{\textquoteright}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.",

author = "Andrea Stojakovic and Sergey Trushin and Anthony Sheu and Layla Khalili and Chang, {Su Youne} and Xing Li and Trace Christensen and Salisbury, {Jeffrey L.} and Geroux, {Rachel E.} and Benjamin Gateno and Flannery, {Padraig J.} and Mrunal Dehankar and Funk, {Cory C.} and Jordan Wilkins and Anna Stepanova and Tara O{\textquoteright}Hagan and Alexander Galkin and Jarred Nesbitt and Xiujuan Zhu and Utkarsh Tripathi and Slobodan Macura and Tamar Tchkonia and Tamar Pirtskhalava and Kirkland, {James L.} and Kudgus, {Rachel A.} and Schoon, {Renee A.} and Reid, {Joel M.} and Yu Yamazaki and Takahisa Kanekiyo and Song Zhang and Emirhan Nemutlu and Petras Dzeja and Adam Jaspersen and Kwon, {Ye In Christopher} and Lee, {Michael K.} and Eugenia Trushina",

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{\textquoteright}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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s42003-020-01584-y",

language = "English (US)",

volume = "4",

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T1 - Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

AU - Stojakovic, Andrea

AU - Trushin, Sergey

AU - Sheu, Anthony

AU - Khalili, Layla

AU - Chang, Su Youne

AU - Li, Xing

AU - Christensen, Trace

AU - Salisbury, Jeffrey L.

AU - Geroux, Rachel E.

AU - Gateno, Benjamin

AU - Flannery, Padraig J.

AU - Dehankar, Mrunal

AU - Funk, Cory C.

AU - Wilkins, Jordan

AU - Stepanova, Anna

AU - O’Hagan, Tara

AU - Galkin, Alexander

AU - Nesbitt, Jarred

AU - Zhu, Xiujuan

AU - Tripathi, Utkarsh

AU - Macura, Slobodan

AU - Tchkonia, Tamar

AU - Pirtskhalava, Tamar

AU - Kirkland, James L.

AU - Kudgus, Rachel A.

AU - Schoon, Renee A.

AU - Reid, Joel M.

AU - Yamazaki, Yu

AU - Kanekiyo, Takahisa

AU - Zhang, Song

AU - Nemutlu, Emirhan

AU - Dzeja, Petras

AU - Jaspersen, Adam

AU - Kwon, Ye In Christopher

AU - Lee, Michael K.

AU - Trushina, Eugenia

N1 - 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).

PY - 2021/12

Y1 - 2021/12

N2 - 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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Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

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