POSITIVE CORRELATION BETWEEN ELEVATED PLASMA CHOLESTEROL LEVELS AND COGNITIVE IMPAIRMENTS IN LDL RECEPTOR KNOCKOUT MICE: RELEVANCE OF CORTICO-CEREBRAL MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS

Convergent epidemiological, clinical, and experimental findings indicate that hypercholesterolemia contributes to the onset of Alzheimer's disease (AD)-like dementia, but the exact underlying mechanisms remains unknown. In this study, we evaluated the cognitive performance of mice submitted to a model of hypercholesterolemia, as well as its relationship with mitochondrial dysfunction and oxidative stress, two key events involved in AD pathogenesis. Wildtype C57bI/6 or low density lipoprotein receptor (LDLr)-deficient mice were fed with either standard or cholesterol-enriched diet for a 4-week period and tested for spatial learning and memory in the object location task. LDLr-/- mice displayed spatial learning and memory impairments regardless of diet. Moreover, LDLr-/- mice fed cholesterol-enriched diet presented a significant decrease in the mitochondrial complexes I and II activities in the cerebral cortex, which were negatively correlated with respective blood cholesterol levels. Additionally, hypercholesterolemic LDLr-/- mice presented a significant decrease in glutathione levels, about 40% increase in the thiobarbituric acid-reactive substances levels, as well as an imbalance between the peroxide-removing-related enzymes glutathione peroxidase/glutathione reductase activities in the cerebral cortex. These findings indicate a significant relationship between hypercholesterolemia, cognitive impairment, and cortico-cerebral mitochondrial dysfunctional/oxidative stress. Because of the involvement of such alterations in AD patients, our data render this mouse model of hypercholesterolemia a useful approach to comprehend the molecular events mediating AD pathogenesis. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.