TY - JOUR
T1 - Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β- peptide
T2 - Role of the lipid peroxidation product 4-hydroxynonenal
AU - Keller, Jeffrey N.
AU - Pang, Zheng
AU - Geddes, James W.
AU - Begley, James G.
AU - Germeyer, Ariane
AU - Waeg, Georg
AU - Mattson, Mark P.
PY - 1997/7
Y1 - 1997/7
N2 - 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.
AB - 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.
KW - ATP
KW - Alzheimer's disease
KW - Cerebral cortex
KW - Excitotoxicity
KW - Malondialdehyde
KW - Mitochondrial respiration
KW - Superoxide anion radical
KW - Synaptic metabolism
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U2 - 10.1046/j.1471-4159.1997.69010273.x
DO - 10.1046/j.1471-4159.1997.69010273.x
M3 - Article
C2 - 9202320
AN - SCOPUS:0030966546
SN - 0022-3042
VL - 69
SP - 273
EP - 284
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 1
ER -