High cholesterol diet down regulates the activity of activator protein-1 but not nuclear factor-kappa B in rabbit brain

Cardiovascular risk factors and alterations in cholesterol metabolism are i mplicated in the pathogenesis of Alzheimer's dementia (AD). The hypercholes terolemic rabbit model of atheroslerosis and AD was utilized in this study to examine oxidative stress related changes in the brain. The high choleste rol diet induced dramatic increases in plasma and liver cholesterol concent rations, but brain cholesterol levels remained constant. Similar effects ha ve been found regarding lipid oxidation products. The amounts of conjugated dienes, trienes and thiobstrbituric acid reactive substances (TBARS) signi ficantly increased in the plasma of cholesterol treated animals while the b rain cortex showed no signs of increased lipid peroxidation. The oxidative damage sensitive nuclear transcription factor kappa B (NF-KB) and activator protein-1 (AP-1) diverged in their responses. Accordingly, the AP-1 DNA bi nding activity decreased by more than 50% in brain nuclear protein extracts while the NF-KB binding activity remained unaltered by the hypercholestero l diet. These results indicate that despite the relative resistance of the central nervous system to dietary manipulation of its lipid composition and lipid peroxidation products, chronic dietary intake of cholesterol can alt er the function of certain proteins involved in regulation of gene expressi on in the brain. (C) 2001 Elsevier Science Inc. All rights reserved.