Background: High cholesterol aggravates the risk development of Alzheimer's disease
(AD). AD is closely related to the transport impairment of Amyloid-β (Aβ) in the blood-brain barrier.
It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aβ
transport. The purpose of the study is to investigate whether high cholesterol regulates Aβ transport
through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation
End products (RAGE) in the risk development of AD.
Methods: We established high cholesterol AD mice model. The learning and memory functions were
evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated,
cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect
on Aβ transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured
microvessels after using Wnt inhibitor DKK-1 and β-catenin inhibitor XAV-939.
Results: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia
increased serum Aβ40 level, while serum Aβ42 level did not change significantly. Hypercholesterolemia
decreased LRP1 expression and increased RAGE expression in cerebral microvascular
endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment,
high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aβ40 expression
in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1
and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/β-catenin signaling
Conclusion: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral
microvascular endothelial cells, which led to Aβ transport disorder in the blood-brain barrier. Increased
Aβ deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD