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From the Department of Chemistry (Dr. Lovell), Departments of Pathology and Neurology (Dr. Markesbery), and the Sanders-Brown Center on Aging (Drs. Lovell, Xie, and Markesbery), University of Kentucky, Lexington, KY.
Address correspondence and reprint requests to Dr. William R. Markesbery, 101 Sanders-Brown Building, University of Kentucky, Lexington, KY 40536-0230.
Objective: To investigate the levels of glutathione transferase (GST), a protective enzyme against aldehydes, and especially 4-hydroxynonenal (HNE) in the brain and ventricular CSF of autopsied AD and normal control subjects.
Background: Studies have implicated increased levels of oxidative stress in the brain in the pathogenesis of AD. Decreased levels of polyunsaturated fatty acids and increased levels of markers of lipid peroxidation have been reported in the brain in AD, particularly in areas severely affected in the disease. HNE, one marker of lipid peroxidation, is neurotoxic in neuronal culture and in vivo and is elevated in AD brain and CSF.
Methods: We measured levels of GST activity and protein in multiple brain regions and ventricular CSF in short-postmortem-interval AD patients and age-matched prospectively evaluated control subjects.
Results: A decrease in GST activity in all brain areas was observed in AD compared with controls with significant decreases in the amygdala, hippocampus and parahippocampal gyrus, inferior parietal lobule, and nucleus basalis of Meynert. Levels of GST protein also were depleted in most brain regions in AD. A significant decrease in GST activity and protein levels was also found in ventricular CSF in AD.
Conclusion: Reduced levels of GST, a protective mechanism against HNE, may have a role in the pathogenesis of neuron degeneration in AD.
Funding for this work was provided by NIH grants 1-P01-AG05119 and 5-P50-AG05144 and by a grant from the Abercrombie Foundation.
Received May 15, 1998. Accepted in final form August 8, 1998.
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