Effects of lifestyle modifications on cognitive impairments in a mouse model of hypercholesterolemia

Epidemiological studies indicate that high midlife plasma cholesterol levels increases the risk of Alzheimer's disease. Moreover, middle-aged familial hypercholesterolemia (FH) subjects show a particularly high incidence of mild cognitive impairments (MCI). These evidence points to hypercholesterolemia as one of the modifiable risk factors focused on prevention/treatment of cognitive deterioration. The present study draws a comparison between pharmacological (lipid-lowering drug probucol) and non-pharmacological (voluntary running wheel, RW) approaches for the management of hypercholesterolemia and cognitive impairments associated with the low-density lipoprotein receptor-deficient (LDLr(-/-)) mice, a well-established rodent model of FH. We also investigated whether exposure to environmental enrichment (EE), a feasible option to increase physical activity in young mice cohort, from birth to adolescence (PN45) yields long-term behavioral changes in adult LDLr(-/-) mice (PN90). We observed that both probucol and RW significantly decreased total and non-HDL plasma cholesterol levels in LDLr(-/-) mice. Notably, only physical exercise mitigated the spatial memory deficits of LDLr(-/-) mice. In addition, we showed that exposure to EE from birth until the adolescence did not mitigate the spatial memory deficits of adult LDLr(-/-) mice in the object location task, although it induced persistent anxyolitic-like effects in the open field arena. Collectively, our results emphasize the advantages physical exercise, in comparison to lipid-lowering drugs, for the management of cognitive deficits associated with FH.