Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β- peptide: Role of the lipid peroxidation product 4-hydroxynonenal

Jeffrey N. Keller, Zheng Pang, James W. Geddes, James G. Begley, Ariane Germeyer, Georg Waeg, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

431 Scopus citations

Abstract

Deposits of amyloid β-peptide (Aβ), reduced glucose uptake into brain cells, oxidative damage to cellular proteins and lipids, and excitotoxic mechanisms have all been suggested to play roles in the neurodegenerative process in Alzheimer's disease. Synapse loss is closely correlated with cognitive impairments in Alzheimer's disease, suggesting that the synapse may be the site at which degenerative mechanisms are initiated and propagated. We report that Aβ causes oxyradical-mediated impairment of glucose transport, glutamate transport, and mitochondrial function in rat neocortical synaptosomes. Aβ induced membrane lipid peroxidation in synaptosomes that occurred within 1 h of exposure; significant decreases in glucose transport occurred within 1 h of exposure to Aβ and decreased further with time. The lipid peroxidation product 4-hydroxynonenal conjugated to synaptosomal proteins and impaired glucose transport; several antioxidants prevented Aβ- induced impairment of glucose transport, indicating that lipid peroxidation was causally linked to this adverse action of Aβ. FeSO4 (an initiator of lipid peroxidation), Aβ, and 4-hydroxynonenal each induced accumulation of mitochondrial reactive oxygen species, caused concentration-dependent decreases in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, and reduced cellular ATP levels significantly. Aβ also impaired glutamate transport, an effect blocked by antioxidants. These data suggest that Aβ induces membrane lipid peroxidation, which results in impairment of the function of membrane glucose and glutamate transporters, altered mitochondrial function, and a deficit in ATP levels; 4-hydroxynonenal appears to be a mediator of these actions of Aβ. These data suggest that oxidative stress occurring at synapses may contribute to the reduced glucose uptake and synaptic degeneration that occurs in Alzheimer's disease patients. They further suggest a sequence of events whereby oxidative stress promotes excitotoxic synaptic degeneration and neuronal cell death in a variety of different neurodegenerative disorders.

Original languageEnglish
Pages (from-to)273-284
Number of pages12
JournalJournal of Neurochemistry
Volume69
Issue number1
DOIs
StatePublished - Jul 1997

Funding

FundersFunder number
National Institute on AgingP50AG005144

    Keywords

    • ATP
    • Alzheimer's disease
    • Cerebral cortex
    • Excitotoxicity
    • Malondialdehyde
    • Mitochondrial respiration
    • Superoxide anion radical
    • Synaptic metabolism

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

    Fingerprint

    Dive into the research topics of 'Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β- peptide: Role of the lipid peroxidation product 4-hydroxynonenal'. Together they form a unique fingerprint.

    Cite this