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Stojakovic 2021 Commun Biol

From Bioblast
Publications in the MiPMap
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.

Β» PMID: 33420340 Open Access

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) 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.

β€’ Bioblast editor: Plangger M


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Alzheimer's 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 



HRR: Oxygraph-2k 

2021-01