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

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. Hypercholes- terolemia increased serum Aβ40 level, while serum Aβ42 level did not change significantly. Hyper- cholesterolemia 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.

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S1180 XAV-939 XAV-939 (NVP-XAV939) selectively inhibits Wnt/β-catenin-mediated transcription through tankyrase1/2 inhibition with IC50 of 11 nM/4 nM in cell-free assays, regulates axin levels and does not affect CRE, NF-κB or TGF-β. (272) (8)

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