Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.

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 r

SUBMITTER: Zhang L 

PROVIDER: S-EPMC4465115 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature