title: Soluble oligomers of amyloid-β cause changes in redox state, DNA methylation, and gene transcription by inhibiting EAAT3 mediated cysteine uptake.
abstract: Oxidative stress, hyperhomocysteinemia, altered DNA methylation, and insulin resistance in the brain are associated with Alzheimer's disease (AD), but the role of amyloid-β (Aβ) in these events remains unclear. Intracellular cysteine is rate-limiting for synthesis of the antioxidant glutathione (GSH), and factors regulating cysteine uptake exert a powerful influence over cellular redox status, especially in mature neurons where cysteine synthesis via transsulfuration of homocysteine (HCY) is restricted. We investigated the effect of soluble Aβ oligomers (oAβ) on basal and insulin-like growth factor-1 (IGF-1)-induced cysteine uptake mediated by the excitatory amino acid transporter 3 (EAAT3) in cultured human neuronal cells. We also examined the effect of oAβ on intracellular thiol metabolite levels, DNA methylation, and the transcription status of redox and methylation-associated genes. oAβ inhibited EAAT3-mediated cysteine uptake, causing a decrease in intracellular cysteine and GSH levels. The ratio of the methyl donor S-adenosylmethionine to the methylation inhibitor S-adenosylhomocysteine was decreased, in association with an increase in HCY and a global decrease in DNA methylation, indicative of decreased activity of the redox-sensitive enzyme methionine synthase. These metabolic effects of oAβ coincided with changes in the expression of redox and methylation pathway genes. The ability of oAβ to modulate gene expression via their redox and methylation-dependent epigenetic effects may contribute to the pathology of AD and recognition of this mechanism may lead to novel treatment approaches. We describe a role of IGF-1 signaling in regulating redox and methylation homeostasis, and propose this to be a pathogenic target of oAβ.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA. hodgna01@gmail.com
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Hodgson
authors.forename: Malav
authors.initials: M
authors.lastname: Trivedi
authors.forename: Christina
authors.initials: C
authors.lastname: Muratore
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Deth
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D050580:Excitatory Amino Acid Transporter 3; C493400:SLC1A1 protein, human; D007334:Insulin-Like Growth Factor I; D003545:Cysteine