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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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