title: Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress.
abstract: 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. Wild-type C57bl/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.
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: de Oliveira
authors.forename: M A
authors.initials: MA
authors.lastname: Hort
authors.forename: E L G
authors.initials: EL
authors.lastname: Moreira
authors.forename: V
authors.initials: V
authors.lastname: Glaser
authors.forename: R M
authors.initials: RM
authors.lastname: Ribeiro-do-Valle
authors.forename: R D
authors.initials: RD
authors.lastname: Prediger
authors.forename: M
authors.initials: M
authors.lastname: Farina
authors.forename: A
authors.initials: A
authors.lastname: Latini
authors.forename: A F
authors.initials: AF
authors.lastname: de Bem
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002784:Cholesterol / Q000097:blood; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000032:analysis / Q000378:metabolism; D005980:Glutathione Reductase / Q000032:analysis / Q000378:metabolism; D006937:Hypercholesterolemia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D011973:Receptors, LDL / Q000172:deficiency
chemical_list: D011973:Receptors, LDL; D002784:Cholesterol; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase