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.

背景：高胆固醇会加剧阿尔茨海默病 (AD) 的风险发展。AD与血脑屏障中淀粉样蛋白-β（Aβ）的转运障碍密切相关。目前尚不清楚高胆固醇是否通过影响 Aβ 转运来影响 AD 认知障碍的风险。该研究的目的是研究高胆固醇是否通过低密度脂蛋白受体相关蛋白 1 (LRP1) 和高级糖化终产物受体 (RAGE) 调节 AD 风险发展中的 Aβ 转运。

方法：建立高胆固醇AD小鼠模型。学习和记忆功能由莫里斯水迷宫（MWM）评估。分离、培养和观察脑微血管内皮细胞。观察内皮细胞LRP1和RAGE的表达水平及其对体内Aβ转运的影响。在使用 Wnt 抑制剂 DKK-1 和 β-catenin 抑制剂 XAV-939 后，在培养的微血管中检测 LRP1 和 RAGE 的表达水平。

结果：高胆固醇血症加剧了空间学习和记忆障碍。高胆固醇血症增加血清 Aβ40 水平，而血清 Aβ42 水平没有显着变化。高胆固醇血症降低了脑微血管内皮细胞中 LRP1 的表达并增加了 RAGE 的表达。高胆固醇血症增加了 AD 小鼠的脑细胞凋亡。在体外实验中，高胆固醇降低了LRP1的表达，增加了RAGE的表达，增加了脑微血管内皮细胞中Aβ40的表达。高胆固醇通过 Wnt/β-catenin 信号通路调节 LRP1 和 RAGE 的表达以及 LRP1 和 RAGE 启动子的转录活性。

结论：高胆固醇降低脑微血管内皮细胞LRP1表达，增加RAGE表达，导致血脑屏障Aβ转运障碍。脑内 Aβ 沉积增加会加剧脑细胞凋亡，导致 AD 小鼠的认知障碍。