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Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid beta-peptide: role of the lipid peroxidation product 4-hydroxynonenal.
- Source :
-
Journal of neurochemistry [J Neurochem] 1997 Jul; Vol. 69 (1), pp. 273-84. - Publication Year :
- 1997
-
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.
- Subjects :
- Animals
Biological Transport physiology
Cell Membrane metabolism
Cross-Linking Reagents metabolism
Energy Metabolism physiology
Female
Lipid Peroxidation physiology
Mitochondria metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species metabolism
Synapses chemistry
Synapses metabolism
Synaptosomes metabolism
Aldehydes metabolism
Amyloid beta-Peptides metabolism
Glucose metabolism
Glutamic Acid metabolism
Oxidative Stress physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3042
- Volume :
- 69
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9202320
- Full Text :
- https://doi.org/10.1046/j.1471-4159.1997.69010273.x