Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In
this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in
low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia.
Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6
wild-type and LDLr–/– mice.
Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/– mice were
submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi.
Results: A tenfold elevation in plasma cholesterol levels of LDLr–/– mice was observed after a hypercholesterolemic diet,
while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and
did not induce cognitive impairment. LDLr–/– mice presented memory impairment regardless of the diet. We observed BBB
disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on
hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/– mice treated with a hypercholesterolemic
diet. The LDLr–/– mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the
hippocampi of LDLr–/– mice was related to high microvessel content and intense astrogliosis, which did not occur in the
control mice.
Conclusion: Therefore, LDLr–/– mice seem to be more susceptible to cognitive impairments and BBB damage induced by
exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced
brain alterations
