AMYLOID BETA-PEPTIDE IMPAIRS GLUCOSE-TRANSPORT IN HIPPOCAMPAL AND CORTICAL-NEURONS - INVOLVEMENT OF MEMBRANE LIPID-PEROXIDATION

A deficit in glucose uptake and a deposition of amyloid beta-peptide ( A beta) each occur in vulnerable brain regions in Alzheimer's disease (AD). It is not known whether mechanistic links exist between A beta d eposition and impaired glucose transport. We now report that A beta im pairs glucose transport in cultured rat hippocampal and cortical neuro ns by a mechanism involving membrane lipid peroxidation. A beta impair ed H-3-deoxy-glucose transport in a concentration-dependent manner and with a time course preceding neurodegeneration. The decrease in gluco se transport was followed by a decrease in cellular ATP levels. Impair ment of glucose transport, ATP depletion, and cell death were each pre vented in cultures pretreated with antioxidants. Exposure to FeSO4, an established inducer of lipid peroxidation, also impaired glucose tran sport. Immunoprecipitation and Western blot analyses showed that expos ure of cultures to A beta induced conjugation of 4-hydroxynonenal (HNE ), an aldehydic product of lipid peroxidation, to the neuronal glucose transport protein GLUT3. HNE induced a concentration-dependent impair ment of glucose transport and subsequent ATP depletion. Impaired gluco se transport was not caused by a decreased energy demand in the neuron s, because ouabain, which inhibits Na+/K+-ATPase activity and thereby reduces neuronal ATP hydrolysis rate, had little or no effect on gluco se transport. Collectively, the data demonstrate that lipid peroxidati on mediates A beta-induced impairment of glucose transport in neurons and suggest that this action of A beta may contribute to decreased glu cose uptake and neuronal degeneration in AD.