title: ApoB100/LDLR-/- hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage.
abstract: Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD). Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions) concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing) and impairment of the episodic-like memory (determined by the integrated memory test). This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.
authors.affiliation: BioPharma Division, Neuron BPh, Granada, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ramírez
authors.forename: Saleta
authors.initials: S
authors.lastname: Sierra
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Tercero
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Vázquez
authors.forename: Antonia
authors.initials: A
authors.lastname: Pineda
authors.forename: Tatiana
authors.initials: T
authors.lastname: Manrique
authors.forename: Javier S
authors.initials: JS
authors.lastname: Burgos
mesh_terms: D000686:Amyloidosis / Q000209:etiology / Q000473:pathology; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000473:pathology; D053299:Apolipoprotein B-100 / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology; D001522:Behavior, Animal; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D006720:Homozygote; D006937:Hypercholesterolemia / Q000209:etiology* / Q000473:pathology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D011973:Receptors, LDL / Q000502:physiology*
chemical_list: D053299:Apolipoprotein B-100; D011973:Receptors, LDL; D002784:Cholesterol