Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease

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 D Bu, Benjamin Gateno, Kyeong Ok Chang, Karl A Nath, Emirhan Nemutlu, Petras P Dzeja, Yuan-Ping Pang, Duy H. Hua, Eugenia D Trushina

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)294-305
Number of pages12
JournalEBioMedicine
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • Alzheimer's disease
  • AMPK
  • Amyloid beta
  • Animal models of familial AD
  • Axonal trafficking
  • Cellular energetics
  • GSK3beta
  • Hyperphosphorylated tau
  • Mitochondrial complex I activity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Zhang, L., Zhang, S., Maezawa, I., Trushin, S., Minhas, P., Pinto, M., Jin, L. W., Prasain, K., Nguyen, T. D. T., Yamazaki, Y., Kanekiyo, T., Bu, G. D., Gateno, B., Chang, K. O., Nath, K. A., Nemutlu, E., Dzeja, P. P., Pang, Y-P., Hua, D. H., & Trushina, E. D. (2015). Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease. EBioMedicine, 2(4), 294-305. https://doi.org/10.1016/j.ebiom.2015.03.009