| Literature DB >> 33420340 |
Andrea Stojakovic1, Sergey Trushin1, Anthony Sheu2, Layla Khalili1, Su-Youne Chang3,4, Xing Li5, Trace Christensen6, Jeffrey L Salisbury6,7, Rachel E Geroux1, Benjamin Gateno1, Padraig J Flannery1, Mrunal Dehankar5, Cory C Funk8, Jordan Wilkins1, Anna Stepanova9, Tara O'Hagan9, Alexander Galkin9, Jarred Nesbitt1, Xiujuan Zhu1, Utkarsh Tripathi1, Slobodan Macura7, Tamar Tchkonia10, Tamar Pirtskhalava10, James L Kirkland10, Rachel A Kudgus11, Renee A Schoon11, Joel M Reid11, Yu Yamazaki12, Takahisa Kanekiyo12, Song Zhang13, Emirhan Nemutlu14, Petras Dzeja13, Adam Jaspersen6, Ye In Christopher Kwon2, Michael K Lee2, Eugenia Trushina15,16.
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.Entities:
Year: 2021 PMID： 33420340 PMCID： PMC7794523 DOI： 10.1038/s42003-020-01584-y
Source DB: PubMed Journal: Commun Biol ISSN： 2399-3642