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

doi:10.2174/1567205018666210906092940

摘要

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。

关键词: 阿尔茨海默病、高胆固醇、低密度脂蛋白受体相关蛋白、晚期糖基化终产物受体、β淀粉样蛋白、血脑屏障。

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DOI https://dx.doi.org/10.2174/1567205018666210906092940	Print ISSN 1567-2050
Publisher Name Bentham Science Publisher	Online ISSN 1875-5828

当代阿耳茨海默病研究

阿尔茨海默病、β-淀粉样蛋白、中性粒细胞、β-淀粉样蛋白降解酶、生物活性肽、神经毒性。

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当代阿耳茨海默病研究

阿尔茨海默病、β-淀粉样蛋白、中性粒细胞、β-淀粉样蛋白降解酶、生物活性肽、神经毒性。

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