title: Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes.
abstract: Oxidative stress plays an important role in the progression of Alzheimer's disease (AD) and other neurodegenerative conditions. Glutathione (GSH), the major antioxidant in the central nervous system, is primarily synthesized and released by astrocytes. We determined if β-amyloid (Aβ42), crucially involved in Alzheimer's disease, affected GSH release. Monomeric Aβ (mAβ) stimulated GSH release from cultured cortical astrocytes more effectively than oligomeric Aβ (oAβ) or fibrillary Aβ (fAβ). Monomeric Aβ increased the expression of the transporter ABCC1 (also referred to as MRP1) that is the main pathway for GSH release. GSH release from astrocytes, with or without mAβ stimulation, was reduced by pharmacological inhibition of ABCC1. Astrocytes robustly express connexin proteins, especially connexin43 (Cx43), and mAβ also stimulated Cx43 hemichannel-mediated glutamate and GSH release. Aβ-stimulation facilitated hemichannel opening in the presence of normal extracellular calcium by reducing astrocyte cholesterol level. Aβ treatment did not alter the intracellular concentration of reduced or oxidized glutathione. Using a mouse model of AD with early onset Aβ deposition (5xFAD), we found that cortical ABCC1 was significantly increased in temporal register with the surge of Aβ levels in these mice. ABCC1 levels remained elevated from 1.5 to 3.5 months of age in 5xFAD mice, before plunging to subcontrol levels when amyloid plaques appeared. Similarly, in cultured astrocytes, prolonged incubation with aggregated Aβ, but not mAβ, reduced induction of ABCC1 expression. These results support the hypothesis that in the early stage of AD pathogenesis, less aggregated Aβ increases GSH release from astrocytes (via ABCC1 transporters and Cx43 hemichannels) providing temporary protection from oxidative stress which promotes AD development.
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Union Hospital of Fujian Medical University, Fuzhou, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Ye
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Union Hospital of Fujian Medical University, Fuzhou, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Union Hospital of Fujian Medical University, Fuzhou, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Union Hospital of Fujian Medical University, Fuzhou, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
authors.forename: Yuan-Gui
authors.initials: YG
authors.lastname: Zhu
authors.affiliation: Department of Neurology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ransom
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Union Hospital of Fujian Medical University, Fuzhou, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of Washington School of Medicine, Seattle, Washington.|Center for Neuroscience Research, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
authors.forename: Zu-Cheng
authors.initials: ZC
authors.lastname: Ye
mesh_terms: D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D058225:Plaque, Amyloid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium; D002784:Cholesterol; D018031:Connexin 43; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C543076:GJA1 protein, mouse; C421109:multidrug resistance-associated protein 1
keywords: ABCC1; Alzheimer's disease; cholesterol; connexin hemichannel; glutathione; β-amyloid