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

Stojakovic, Andrea; Trushin, Sergey; Sheu, Anthony; Khalili, Layla; Chang, Su-Youne; Li, Xing; Christensen, Trace; Salisbury, Jeffrey; Geroux, Rachel; Gateno, Benjamin; Flannery, Padraig; Dehankar, Mrunal; Funk, Cory; Wilkins, Jordan; Stepanova, Anna; O'Hagan, Tara; Galkin, Alexander; Nesbitt, Jarred; Zhu, Xiujuan; Tripathi, Utkarsh; Macura, Slobodan; Tchkonia, Tamar; Pirtskhalava, Tamar; Kirkland, James; Kudgus, Rachel; Schoon, Renee; Reid, Joel; Yamazaki, Yu; Kanekiyo, Takahisa; Zhang, Song; NEMUTLU, EMİRHAN; Dzeja, Petras; Jaspersen, Adam; Kwon, Ye; Lee, Michael; Trushina, Eugenia

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

Atıf İçin Kopyala

Stojakovic A., Trushin S., Sheu A., Khalili L., Chang S., Li X., ...Daha Fazla

COMMUNICATIONS BIOLOGY, cilt.4, sa.1, 2021 (SCI-Expanded)

Yayın Türü: Makale / Tam Makale
Cilt numarası: 4 Sayı: 1
Basım Tarihi: 2021
Doi Numarası: 10.1038/s42003-020-01584-y
Dergi Adı: COMMUNICATIONS BIOLOGY
Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE, Directory of Open Access Journals
Hacettepe Üniversitesi Adresli: Evet

Özet

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, P-31 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. Andrea Stojakovic et al. demonstrate that partial pharmacological inhibitor of mitochondrial complex I (CP2) can reduce neurodegeneration and improve key disease phenotypes in a symptomatic mouse model of Alzheimer's disease.