title: Apolipoprotein E4 Elicits Lysosomal Cathepsin D Release, Decreased Thioredoxin-1 Levels, and Apoptosis.
abstract: The major genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (ApoE4), has been suggested to have detrimental effects on neurons, including direct toxicity via apoptosis. Thioredoxin-1 (Trx1) is an endogenous antioxidant protein important for redox regulation and participates in the regulation of apoptosis through the inhibition of apoptosis signal-regulating kinase-1 (Ask-1). In this study, we have investigated the effects of ApoE on Trx1 in the brain. Our results showed that the protein levels of Trx1 were reduced in the hippocampus of ApoE4 targeted replacement (TR) mice compared to ApoE3 TR mice. The reduction was also seen in vitro after treatment of both human primary cortical neurons and neuroblastoma cells with human recombinant ApoE4 (rApoE4). Furthermore, ApoE4 caused a disruption of lysosomal integrity and a shift in the localization of Cathepsin D, an enzyme known to degrade Trx1. ApoE4 treatment induced in addition apoptosis through translocation of Death-domain associated protein-6 (Daxx) from the nucleus to the cytosol, suggesting an activation of the Ask-1 pathway. This toxicity was prevented by overexpression of Trx1 and other endogenous Ask-1 inhibitors. Our data suggests that down-regulation of Trx1 is involved in the toxicity caused by ApoE4. An activated ASK-1 pathway might indeed make cells more vulnerable to other insults such as amyloid-β, which could partially explain the mechanism behind the strongest genetic risk factor for AD.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Persson
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lattanzio
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Javier
authors.initials: J
authors.lastname: Calvo-Garrido
authors.affiliation: Department-DIMEC-University of Bologna, Medical and Surgical Science, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Marta
authors.initials: M
authors.lastname: Rubio-Rodrigo
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Sundström
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maioli
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Sandebring-Matton
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Cedazo-Mínguez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002402:Cathepsin D / Q000378:metabolism*; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D056970:Co-Repressor Proteins; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D013879:Thioredoxins; D048848:MAP Kinase Kinase Kinase 5; D002402:Cathepsin D
keywords: Alzheimer’s disease; apolipoprotein E4; apoptosis; cathepsin D; lysosomes; thioredoxins