title: Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria.
abstract: Brain accumulation of the amyloid-β peptide (Aβ) and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD). Hexokinase (HK), a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS) generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.
authors.affiliation: Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Saraiva
authors.forename: Gisele S
authors.initials: GS
authors.lastname: Seixas da Silva
authors.forename: Antonio
authors.initials: A
authors.lastname: Galina
authors.forename: Wagner S
authors.initials: WS
authors.lastname: da-Silva
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.forename: Sérgio T
authors.initials: ST
authors.lastname: Ferreira
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: De Felice
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D003847:Deoxyglucose; C472074:HK1 protein, human; D006593:Hexokinase; C022616:thiazolyl blue