Effect of High Cholesterol Regulation of LRP1 and RAGE on Aβ Transport Across the Blood-Brain Barrier in Alzheimer's Disease.

Abstract

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 pathway.

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 mice.

• Authors: Rui Zhou, Li-Li Chen, Hai Yang, Ling Li, Juan Liu, Le Chen, Wen-Juan Hong, Cong-Guo Wang, Jing-Jing Ma, Jie Huang, Xin-Fu Zhou, Dong Liu, Hua-Dong Zhou
• Journal: Current Alzheimer research (Curr Alzheimer Res) Vol. 18 Issue 5 Pg. 428-442 ( 2021) ISSN: 1875-5828 [Electronic] United Arab Emirates
• PMID: 34488598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Amyloid beta-Peptides
• LRP1 protein, human
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• Peptide Fragments
• Receptor for Advanced Glycation End Products
• amyloid beta-protein (1-40)
• Cholesterol

Topics

• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Cholesterol (pharmacology)
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Humans
• Hypercholesterolemia
• Low Density Lipoprotein Receptor-Related Protein-1 (metabolism)
• Mice
• Peptide Fragments
• Receptor for Advanced Glycation End Products (metabolism)