title: Astrocytic redox remodeling by amyloid beta peptide.
abstract: Astrocytes are critical for neuronal redox homeostasis providing them with cysteine needed for glutathione synthesis. In this study, we demonstrate that the astrocytic redox response signature provoked by amyloid beta (Aβ) is distinct from that of a general oxidant (tertiary-butylhydroperoxide [t-BuOOH]). Acute Aβ treatment increased cystathionine β-synthase (CBS) levels and enhanced transsulfuration flux in contrast to repeated Aβ exposure, which decreased CBS and catalase protein levels. Although t-BuOOH also increased transsulfuration flux, CBS levels were unaffected. The net effect of Aβ treatment was an oxidative shift in the intracellular glutathione/glutathione disulfide redox potential in contrast to a reductive shift in response to peroxide. In the extracellular compartment, Aβ, but not t-BuOOH, enhanced cystine uptake and cysteine accumulation, and resulted in remodeling of the extracellular cysteine/cystine redox potential in the reductive direction. The redox changes elicited by Aβ but not peroxide were associated with enhanced DNA synthesis. CBS activity and protein levels tended to be lower in cerebellum from patients with Alzheimer's disease than in age-matched controls. Our study suggests that the alterations in astrocytic redox status could compromise the neuroprotective potential of astrocytes and may be a potential new target for therapeutic intervention in Alzheimer's disease.
authors.affiliation: Department of Biochemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Garg
authors.forename: Victor
authors.initials: V
authors.lastname: Vitvitsky
authors.forename: Roger
authors.initials: R
authors.lastname: Albin
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D003553:Cystine / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D017382:Reactive Oxygen Species; D003553:Cystine; D004247:DNA; D020122:tert-Butylhydroperoxide; D003541:Cystathionine beta-Synthase; D003545:Cysteine