Abstract：
Preclinical and clinical studies have indicated that compromised blood-brain barrier (BBB) function contributes to Alzheimer\'s disease (AD) pathology. BBB breakdown ranged from mild disruption of tight junctions (TJs) with increased BBB permeability to chronic integrity loss, affecting transport across the BBB, reducing brain perfusion, and triggering inflammatory responses. We recently developed a high-throughput screening (HTS) assay to identify hit compounds that enhance the function of a cell-based BBB model. The HTS screen identified (S,E)-2-acetyl-6-[3-(4\'-fluorobiphenyl-4-yl)acryloyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo-[b,d]furan-1(9bH)-one (4-FPBUA), a semisynthetic analogue of naturally occurring usnic acid, which protected the in vitro model against Aβ toxicity. Usnic acid is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton that is commonly found in lichenized fungi of the genera Usnea. In this study, we aimed to evaluate the effect of 4-FPBUA in vitro on the cell-based BBB model function and its in vivo ability to rectify BBB function and reduce brain Aβ in two AD mouse models, namely, 5xFAD and TgSwDI. Our findings demonstrated that 4-FPBUA enhanced cell-based BBB function, increased Aβ transport across the monolayer, and reversed BBB breakdown in vivo by enhancing autophagy as an mTOR inhibitor. Induced autophagy was associated with a significant reduction in Aβ accumulation and related pathologies and improved memory function. These results underscore the potential of 4-FPBUA as a candidate for further preclinical exploration to better understand its mechanisms of action and to optimize dosing strategies. Continued research may also elucidate additional pathways through which 4-FPBUA contributed to the amelioration of BBB dysfunction in AD. Collectively, our findings supported the development of 4-FPBUA as a therapeutic agent against AD.
摘要：
临床前和临床研究表明，受损的血脑屏障（BBB）功能有助于阿尔茨海默病（AD）病理。BBB破坏范围从轻度破坏紧密连接（TJ）增加的BBB通透性到慢性完整性丧失。影响跨BBB的运输，减少脑灌注，并引发炎症反应。我们最近开发了一种高通量筛选（HTS）测定法，以鉴定增强基于细胞的BBB模型功能的命中化合物。HTS屏幕标识(S,E)-2-乙酰基-6-[3-(4'-氟联苯-4-基)丙烯酰基]-3,7,9-三羟基-8,9b-二甲基二苯并-[b,d]呋喃-1(9bH)-one(4-FPBUA)，一种天然存在的松果酸的半合成类似物，保护体外模型免受Aβ毒性。松酸是地衣衍生的次生代谢产物，具有独特的二苯并呋喃骨架，通常在松内属的地衣真菌中发现。在这项研究中,我们旨在评估4-FPBUA在体外对基于细胞的BBB模型功能的影响及其在两种AD小鼠模型中纠正BBB功能和减少脑Aβ的体内能力，即,5xFAD和TgSwDI。我们的研究结果表明，4-FPBUA增强了基于细胞的BBB功能，Aβ跨单层转运增加，并通过增强自噬作为mTOR抑制剂在体内逆转BBB分解。诱导的自噬与Aβ积累和相关病理的显着减少以及记忆功能的改善有关。这些结果强调了4-FPBUA作为进一步临床前探索的候选者的潜力，以更好地了解其作用机制并优化给药策略。持续的研究还可能阐明4-FPBUA有助于改善AD中BBB功能障碍的其他途径。总的来说，我们的研究结果支持4-FPBUA作为抗AD治疗剂的发展.
