Cited by 440Alzheimer's disease research and treatmentsMitochondrial Function and PathologyAntioxidant Activity and Oxidative Stress

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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

Keller, Jeffrey N., Pang, Zheng, Geddes, James W., Begley, James G., Germeyer, Ariane, Waeg, Georg, Mattson, Mark P.·1997·Journal of Neurochemistry

DOI 10.1046/j.1471-4159.1997.69010273.x

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Abstract

Deposits of amyloid beta-peptide (A beta), 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 A beta causes oxyradical-mediated impairment of glucose transport, glutamate transport, and mitochondrial function in rat neocortical synaptosomes. A beta 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 A beta and decreased further with time. The lipid peroxidation product 4-hydroxynonenal conjugated to synaptosomal proteins and impaired glucose transport; several antioxidants prevented A beta-induced impairment of glucose transport, indicating that lipid peroxidation was causally linked to this adverse action of A beta. FeSO4 (an initiator of lipid peroxidation), A beta, 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. A beta also impaired glutamate transport, an effect blocked by antioxidants. These data suggest that A beta 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 A beta. 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.

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Authors: Keller, J. N., Pang, Z., Geddes, J. W., Begley, J. G., Germeyer, A., Waeg, G., & Mattson, M. P.
Affiliations: University of Kentucky (US)
University of Graz (AT)
Corresponding author: Mattson, Mark P.
ORCID: Keller, Jeffrey N.
Geddes, James W.
Germeyer, Ariane
Mattson, Mark P.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 1997-07
Volume: 69
Issue: 1
Pages: 273-284
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1046/j.1471-4159.1997.69010273.x
OpenAlex: W2069303994
Cited by: 439
References: 0
Citations by year: 2025: 3 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 10 · 2018: 14 · 2017: 4 · 2016: 20 · 2015: 10 · 2014: 8 · 2013: 12 · 2012: 15
FWCI: 19.53
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1966 d)
Locations: Journal of Neurochemistry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ns030583-04)
National Institute on Aging (P50AG005144, AG-05144, P01AG010836, AG 10836)
National Institute of Neurological Disorders and Stroke (NS30583)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords: amyloid-beta, Alzheimer's disease, 4-hydroxynonenal, lipid peroxidation, glucose transport, glutamate uptake, mitochondrial dysfunction, oxidative stress, synaptosomes, reactive oxygen species, ATP depletion, synaptic degeneration, excitotoxicity, antioxidants, neurodegeneration
MeSH terms: Aldehydes, Animals, Biological Transport, Cell Membrane, Cross-Linking Reagents, Energy Metabolism, Female, Glucose, Mitochondria, Synapses, Synaptosomes, Lipid Peroxidation, Amyloid beta-Peptides, Rats, Sprague-Dawley, Reactive Oxygen Species, Oxidative Stress, Glutamic Acid, Rats

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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

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