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

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dc.citation.doi10.1016/j.ebiom.2015.03.009
dc.citation.epage305
dc.citation.issn2352-3964
dc.citation.issue4
dc.citation.jtitleEBioMedicine
dc.citation.spage294
dc.citation.volume2
dc.contributor.authorZhang, L.
dc.contributor.authorZhang, S.
dc.contributor.authorMaezawa, I.
dc.contributor.authorTrushin, S.
dc.contributor.authorMinhas, P.
dc.contributor.authorPinto, M.
dc.contributor.authorJin, L. W.
dc.contributor.authorPrasain, K.
dc.contributor.authorNguyen, Thi D.T.
dc.contributor.authorYamazaki, Y.
dc.contributor.authorKanekiyo, T.
dc.contributor.authorBu, G.
dc.contributor.authorGateno, B.
dc.contributor.authorChang, Kyeong-ok
dc.contributor.authorNath, K. A.
dc.contributor.authoreidkchang
dc.date.accessioned2016-04-04T22:45:09Z
dc.date.available2016-04-04T22:45:09Z
dc.date.issued2015-04-01
dc.date.published2015
dc.descriptionCitation: Zhang, L., Zhang, S., Maezawa, I., Trushin, S., Minhas, P., Pinto, M., . . . Trushina, E. (2015). Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease. EBioMedicine, 2(4), 294-305. doi:10.1016/j.ebiom.2015.03.009
dc.descriptionDevelopment 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 3? 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. © 2015.
dc.descriptionAdditional Authors: Nemutlu, E.;Dzeja, P.;Pang, Y. P.;Hua, D. H.;Trushina, E.
dc.identifier.urihttp://hdl.handle.net/2097/32294
dc.relation.urihttps://doi.org/10.1016/j.ebiom.2015.03.009
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAlzheimer'S Disease
dc.subjectAmpk
dc.subjectAmyloid Beta
dc.subjectAnimal Models Of Familial Ad
dc.subjectAxonal Trafficking
dc.subjectCellular Energetics
dc.titleModulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease
dc.typeArticle

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