Stojakovic 2021 Commun Biol
|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. Commun Biol 4:61.|
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 (2021) Commun Biol
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.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Alzheimer's
Organism: Mouse Tissue;cell: Nervous system Preparation: Isolated mitochondria