amyloid-β triggers the release of neuronal hexokinase 1 from mitochondriaamyloid-β触发从线粒体释放神经己糖激酶1.pdfVIP

Amyloid-b Triggers the Release of Neuronal Hexokinase 1 from Mitochondria 1 1 1 1 2 Leonardo M. Saraiva , Gisele S. Seixas da Silva , Antonio Galina , Wagner S. da-Silva , William L. Klein , ´ 1, Fernanda G. De Felice1,2* Sergio T. Ferreira ´ ´ ´ ´ 1 Programa de Bioquımica e Biofısica Celular, Instituto de Bioquımica Medica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil, 2 Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America Abstract Brain accumulation of the amyloid-b peptide (Ab) 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 Ab-induced oxidative stress and HK activity. We found that Ab triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Ab oligomers further impair energy metabolism by decreasing neuronal ATP levels. Ab-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Ab-induced oxidative stress and neuronal death. Results suggest that Ab-induced cellular redistribution and inactivation of neuronal HKI play important roles i