Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2024 Nov 4;21(11):5661-5671. doi: 10.1021/acs.molpharmaceut.4c00633. Epub 2024 Oct 11.
Aβ accumulation in the blood-brain barrier (BBB) endothelium, which lines the cerebrovascular lumen, is a significant contributor to cerebrovascular dysfunction in Alzheimer's disease (AD). Reduced high-density lipoprotein (HDL) levels are associated with increased AD risk, and the HDL mimetic peptide 4F has been developed as a promising therapeutic agent to improve cerebrovascular health in AD. In this study, we evaluated the impact of 4F on I-Aβ blood-to-brain distribution using dynamic SPECT/CT imaging in both wild-type and APP/PS1 transgenic mice. Graphical analysis of the imaging data demonstrated that 4F significantly reduced the blood-to-brain influx rate in wild-type mice and the distribution of I-Aβ in the BBB endothelium in APP/PS1 mice. To elucidate the molecular mechanisms underlying the effect of 4F, we evaluated its impact on the p38 pathway and its role in mediating Aβ trafficking in human BBB endothelial cell monolayers. Treatment with 4F significantly decreased Aβ induced p38 activation in BBB endothelial cells. Furthermore, inhibition of p38 kinase significantly reduced endothelial accumulation of fluorescence-labeled Aβ and luminal-to-abluminal permeability across the cell monolayer. While our previous publication has hinted at the potential of 4F to reduce Aβ accumulation in the brain parenchyma, the current findings demonstrated the protective effect of 4F in reducing Aβ accumulation in the BBB endothelium of AD transgenic mice. These findings revealed the impact of a clinically tested agent, the HDL mimetic peptide 4F, on Aβ exposure to the BBB endothelium and offer novel mechanistic insights into potential therapeutic strategies to treat cerebrovascular dysfunction in AD.
β 淀粉样蛋白（Aβ）在血脑屏障（BBB）内皮细胞中的积累，这些细胞排列在脑血管腔的内表面，是阿尔茨海默病（AD）中脑血管功能障碍的一个重要贡献因素。高密度脂蛋白（HDL）水平降低与 AD 风险增加有关，而 HDL 模拟肽 4F 已被开发为一种有前途的治疗药物，以改善 AD 中的脑血管健康。在这项研究中，我们使用动态 SPECT/CT 成像评估了 4F 对野生型和 APP/PS1 转基因小鼠中 I-Aβ 血脑分布的影响。成像数据的图形分析表明，4F 显著降低了野生型小鼠的血脑流入率和 APP/PS1 小鼠 BBB 内皮中 I-Aβ 的分布。为了阐明 4F 作用的分子机制，我们评估了它对 p38 途径的影响及其在介导人 BBB 内皮细胞单层中 Aβ 转运中的作用。4F 处理显著降低了 BBB 内皮细胞中 Aβ 诱导的 p38 激活。此外，p38 激酶的抑制显著减少了荧光标记的 Aβ 在内皮细胞中的积累和穿过细胞单层的管腔到基底外侧通透性。虽然我们之前的出版物暗示了 4F 降低脑实质中 Aβ 积累的潜力，但目前的研究结果表明 4F 对 AD 转基因小鼠 BBB 内皮中 Aβ 积累的保护作用。这些发现揭示了经过临床测试的药物，即 HDL 模拟肽 4F，对 Aβ 暴露于 BBB 内皮的影响，并为治疗 AD 中脑血管功能障碍的潜在治疗策略提供了新的机制见解。
