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

Deposits of amyloid beta-peptide (A beta), reduced glucose uptake into brain cells, oxidative damage to cellular proteins and lipids, and ex citotoxic mechanisms have all been suggested to play roles in the neur odegenerative process in Alzheimer's disease. Synapse loss is closely correlated with cognitive impairments in Alzheimer's disease, suggesti ng that the synapse may be the site at which degenerative mechanisms a re initiated and propagated. We report that A beta causes oxyradical-m ediated impairment of glucose transport, glutamate transport, and mito chondrial function in rat neocortical synaptosomes. AP induced membran e lipid peroxidation in synaptosomes that occurred within 1 h of expos ure; significant decreases in glucose transport occurred within 1 h of exposure to A beta and decreased further with time. The lipid peroxid ation product 4-hydroxynonenal conjugated to synaptosomal proteins and impaired glucose transport; several antioxidants prevented A beta-ind uced impairment of glucose transport, indicating that lipid peroxidati on was causally linked to this adverse action of A beta. FeSO4 (an ini tiator of lipid peroxidation), A beta, and 4-hydroxynonenal each induc ed accumulation of mitochondrial reactive oxygen species, caused conce ntration-dependent decreases in (4,5-dimethylthiazol-2-yl)-2,5-dipheny ltetrazolium bromide reduction, and reduced cellular ATP levels signif icantly. A beta also impaired glutamate transport, an effect blocked b y 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, an d a deficit in ATP levels; 4-hydroxynonenal appears to be a mediator o f these actions of A beta. These data suggest that oxidative stress oc curring at synapses may contribute to the reduced glucose uptake and s ynaptic degeneration that occurs in Alzheimer's disease patients. They further suggest a sequence of events whereby oxidative stress promote s. excitotoxic synaptic degeneration and neuronal cell death in a vari ety of different neurodegenerative disorders.