Academic Journal
Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease
| العنوان: | Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease |
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| المؤلفون: | Liang Zhang, Song Zhang, Izumi Maezawa, Sergey Trushin, Paras Minhas, Matthew Pinto, Lee-Way Jin, Keshar Prasain, Thi D.T. Nguyen, Yu Yamazaki, Takahisa Kanekiyo, Guojun Bu, Benjamin Gateno, Kyeong-Ok Chang, Karl A. Nath, Emirhan Nemutlu, Petras Dzeja, Yuan-Ping Pang, Duy H. Hua, Eugenia Trushina |
| المصدر: | EBioMedicine, Vol 2, Iss 4, Pp 294-305 (2015) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2015 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Mitochondrial complex I activity, Cellular energetics, Alzheimer's disease, AMPK, Amyloid beta, Hyperphosphorylated tau, GSK3beta, Axonal trafficking, Animal models of familial AD, Medicine, Medicine (General), R5-920 |
| الوصف: | Development of therapeutic strategies to prevent Alzheimer's disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2352-3964 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2352396415000729; https://doaj.org/toc/2352-3964; https://doaj.org/article/89446c32603a429e97abaf9d89ef71a0 |
| DOI: | 10.1016/j.ebiom.2015.03.009 |
| الاتاحة: | https://doi.org/10.1016/j.ebiom.2015.03.009 https://doaj.org/article/89446c32603a429e97abaf9d89ef71a0 |
| رقم الانضمام: | edsbas.4A9B84A |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23523964 |
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| DOI: | 10.1016/j.ebiom.2015.03.009 |