High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr-/- Mice: Impact on Cognitive Function.

Abstract

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.

• Authors: Jade de Oliveira, Daiane F Engel, Gabriela C de Paula, Danúbia B Dos Santos, Jadna B Lopes, Marcelo Farina, Eduardo L G Moreira, Andreza F de Bem
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 78 Issue 1 Pg. 97-115 ( 2020) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 32925052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, LDL
• Cholesterol

Topics

• Animals
• Blood-Brain Barrier
• Cholesterol (metabolism)
• Cognition
• Cognitive Dysfunction (metabolism)
• Diet
• Disease Models, Animal
• Gliosis (metabolism)
• Hippocampus (metabolism)
• Hypercholesterolemia (metabolism)
• Male
• Memory
• Memory Disorders (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Prefrontal Cortex (metabolism)
• Receptors, LDL