TY - JOUR
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 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85098953856&partnerID=8YFLogxK
U2 - 10.1038/s42003-020-01584-y
DO - 10.1038/s42003-020-01584-y
M3 - Article
C2 - 33420340
AN - SCOPUS:85098953856
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 61
ER -