title: 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 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 metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Research, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: MIND Institute and Department of Pathology, University of California Davis, Sacramento, CA 95814, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Trushin
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Paras
authors.initials: P
authors.lastname: Minhas
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pinto
authors.affiliation: MIND Institute and Department of Pathology, University of California Davis, Sacramento, CA 95814, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Keshar
authors.initials: K
authors.lastname: Prasain
authors.affiliation: Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Thi D T
authors.initials: TD
authors.lastname: Nguyen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gateno
authors.affiliation: Department of Diagnostic Medicine Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
authors.affiliation: Department of Nephrology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.affiliation: Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Sihhiye, Ankara, 06100, TURKEY.
authors.forename: Emirhan
authors.initials: E
authors.lastname: Nemutlu
authors.affiliation: Division of Cardiovascular Research, Mayo Clinic Rochester, MN 55905, USA.
authors.forename: Petras
authors.initials: P
authors.lastname: Dzeja
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.affiliation: Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Duy H
authors.initials: DH
authors.lastname: Hua
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA ; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina