RESUMO
BACKGROUND: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-ß (Aß) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aß transport. The purpose of the study is to investigate whether high cholesterol regulates Aß 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 Aß transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and ß-catenin inhibitor XAV-939. RESULTS: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aß40 level, while serum Aß42 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 Aß40 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/ß-catenin signaling pathway. CONCLUSION: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aß transport disorder in the blood-brain barrier. Increased Aß deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.
