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.

Diphenyl diselenide differently modulates cardiovascular redox responses in young adult and middle-aged low-density lipoprotein receptor knockout hypercholesterolemic mice

“…Our results are in line with previous reports, demonstrating no significant differences in lipid profiles between young adult and middle‐aged LDLr −/− mice . However, some studies have showed that aged LDLr −/− mice, instead of the young adult, present evident atheroma plaques of considerable size, suggesting that high cholesterol levels act synergistically with aging in the evolution of atherosclerosis …”

Low‐density Lipoprotein Receptor: A Promising Therapeutic Target to Promote Cerebral Beta‐amyloid Clearance?

“…In this regard, Daniel Zamb on and colleagues [1] recently reported that middle-aged patients with FH exhibit a particularly high incidence of mild cognitive impairment (MCI), a transitional state between the cognitive decline observed in the elderly and proper dementia. Of note, Ramirez and colleagues [2] and we [3] corroborated this observation in ApoB100/LDLr À/À and LDLr À/À experimental mouse models of FH, respectively. Specifically, we found that middle-aged LDLr À/À mice exhibited working, spatial reference, and procedural memory impairments without alterations in exploratory activities and anxiety-related responses.…”

Age-Related Cognitive Decline in Hypercholesterolemic LDL Receptor Knockout Mice (LDLr−/−): Evidence of Antioxidant Imbalance and Increased Acetylcholinesterase Activity in the Prefrontal Cortex

“…Patients with familial hypercholesterolemia tend to have a higher incidence of MCI [77], which was corroborated by experimental studies using a rodent model of familial hypercholesterolemia, the ApoB100/LDLr -/mouse strain [78]. In the present study, we provide new evidence that aged LDLr -/mice, which are exposed to over three-fold cholesterol levels from early life, exhibit working, spatial reference, and procedural memory impairments, without alterations in exploratory activities and anxiety-related responses (data not shown), which were related to impaired function in cognition-relevant brain areas, such as the prefrontal cortex and hippocampus.…”