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Volume 17, Number 3, Issue of February 1, 1997 pp. 1046-1054
Copyright ©1997 Society for Neuroscience

Amyloid -Peptide Impairs Glucose Transport in Hippocampal and Cortical Neurons: Involvement of Membrane Lipid Peroxidation

Received Sept. 25, 1996; revised Nov. 12, 1996; accepted Nov. 14, 1996.

Robert J. Mark¹, Zhen Pang¹, James W. Geddes¹, Koji Uchida², and Mark P. Mattson¹

¹ Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, and ² Laboratory of Food and Biodynamics, Nagoya University, Nagoya, 464-01 Japan

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

Key words: Alzheimer's disease; apoptosis; excitotoxicity; GLUT3; hydroxynonenal; mitochondrial ATP

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