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.
Highlights
In recent years, converging lines of clinical and pathological evidence have indicated a relationship to exist between the deterioration of brain cholesterol homeostasis and the pathophysiology of sporadic Alzheimer’s disease (AD)
It remains unclear whether plasma examined the changes during aging in plasma cholesterol concentration along with the neuropathological and cognitive and psychomotor alterations in a hypercholesterolaemic mouse model that mimics human familial hypercholesterolaemia (FH) [13]
These results are in line with those of epidemiological studies showing that the proportion of patients with FH showing abnormal cognitive function and meeting the criteria for mild cognitive impairment (MCI) is significantly higher than in controls [4]
Summary
In recent years, converging lines of clinical and pathological evidence have indicated a relationship to exist between the deterioration of brain cholesterol homeostasis and the pathophysiology of sporadic AD. Epidemiological studies have shown that hypercholesterolaemia is an early (rather than a late) risk factor for AD, and that elevated plasma concentrations of LDL cholesterol correlate well with the appearance of AD [1,2,3,4]. Patients with familial hypercholesterolaemia (FH) show a high incidence of mild cognitive impairment (MCI), a prodromal stage of abnormal cognitive performance which precedes AD [2,4]. Patients with FH provide a unique window into the role of cholesterol metabolism in cognition. FH is caused by inherited genetic abnormalities that directly or indirectly affect the function of the LDL receptors (LDLRs) [5]. The LDLR family has been implicated in the breakdown of synaptic function in AD [6]
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