Alzheimer’s disease (AD) is the most prevalent cause of dementia characterized by a progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD; however, the development of effective antineuroinflammatory compounds is often hindered by their limited blood-brain barrier (BBB) permeability. Consequently, there is an urgent need for accurate, preclinical AD patient-specific BBB models to facilitate the early identification of immunomodulatory drugs capable of efficiently crossing the human AD BBB. This study presents a unique approach to BBB drug permeability screening as it utilizes the familial AD patient-derived induced brain endothelial-like cell (iBEC)-based model, which exhibits increased disease relevance and serves as an improved BBB drug permeability assessment tool when compared to traditionally employed in vitro models. To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (Cu^II(atsm)) and a library of metal bis(thiosemicarbazone) complexes─a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders. By evaluating the toxicity, cellular accumulation, and permeability of those compounds in the AD patient-derived iBEC, we have identified 3,4-hexanedione bis(N(4)-methylthiosemicarbazonato)copper(II) (Cu^II(dtsm)) as a candidate with good transport across the AD BBB. Furthermore, we have developed a multiplex approach where AD patient-derived iBEC were combined with immune modulators TNFα and IFNγ to establish an in vitro model representing the characteristic neuroinflammatory phenotype at the patient’s BBB. Here, we observed that treatment with Cu^II(dtsm) not only reduced the expression of proinflammatory cytokine genes but also reversed the detrimental effects of TNFα and IFNγ on the integrity and function of the AD iBEC monolayer. This suggests a novel pathway through which copper bis(thiosemicarbazone) complexes may exert neurotherapeutic effects on AD by mitigating BBB neuroinflammation and related BBB integrity impairment. Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD.

中文翻译：

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用于筛选双（缩氨基硫脲）铜配合物作为阿尔茨海默病潜在治疗药物的患者血脑屏障模型

阿尔茨海默氏病 (AD) 是痴呆症的最常见原因，其特征是进行性认知能力下降。解决神经炎症是治疗 AD 的一种有前途的治疗途径；然而，有效的抗神经炎症化合物的开发常常因其有限的血脑屏障（BBB）通透性而受到阻碍。因此，迫切需要准确的临床前 AD 患者特异性 BBB 模型，以促进早期鉴定能够有效穿过人类 AD BBB 的免疫调节药物。这项研究提出了一种独特的 BBB 药物渗透性筛查方法，因为它利用了家族性 AD 患者衍生的诱导脑内皮样细胞 (iBEC) 模型，该模型表现出更高的疾病相关性，并且与比较相比，可作为改进的 BBB 药物渗透性评估工具传统上使用的体外模型。为了证明其作为小分子候选药物筛选平台的实用性，我们研究了二乙酰双( N (4)-缩氨基硫脲)铜(II) (Cu ^II (atsm)) 和金属双(缩氨基硫脲) 配合物库的作用─a在神经退行性疾病中表现出抗神经炎症治疗潜力的一类化合物。通过评估 AD 患者来源的 iBEC 中这些化合物的毒性、细胞蓄积和渗透性，我们将 3,4-己二酮双( N (4)-甲硫基氨基脲)铜 (II) (Cu ^II (dtsm)) 鉴定为交通便利穿过 AD BBB 的候选人。此外，我们还开发了一种多重方法，其中 AD 患者来源的 iBEC 与免疫调节剂 TNFα 和 IFNγ 相结合，建立代表患者 BBB 特征性神经炎症表型的体外模型。在这里，我们观察到 Cu ^II (dtsm) 治疗不仅减少了促炎细胞因子基因的表达，而且还逆转了 TNFα 和 IFNγ 对 AD iBEC 单层完整性和功能的有害影响。这表明双（缩氨基硫脲）铜复合物可能通过减轻 BBB 神经炎症和相关 BBB 完整性损伤而对 AD 发挥神经治疗作用。总之，所提出的模型提供了一个有效且易于扩展的体外BBB 平台，用于筛选 AD 候选药物。其改进的转化潜力使其成为促进旨在调节 AD 神经炎症的金属化合物开发的宝贵工具。