A patient-derived blood-brain barrier model for screening copper bis(thiosemicarbazone) complexes as potential therapeutics in Alzheimer's disease

Abstract

Alzheimers disease (AD) is the most prevalent cause of dementia characterised by progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD, however, the development of effective anti-neuroinflammatory 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 human AD BBB. This study presents a unique approach to BBB drug permeability screening as it utilises the familial AD patient-derived induced brain endothelial-like cells (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 CuII(atsm) and a library of novel metal bis(thiosemicarbazone) complexes - a class of compounds exhibiting anti-neuroinflammatory 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 CuII(dtsm) as an emerging drug candidate with enhanced transport across the AD BBB. Furthermore, we have developed a multiplex approach where AD patient-derived iBEC were combined with immune modulators TNF and IFN{gamma} to establish an in vitro model representing the characteristic neuroinflammatory phenotype at the patients BBB. Here we observed that treatment with CuII(dtsm) not only reduced the expression of proinflammatory cytokine genes but also reversed the detrimental effects of TNF and IFN{psi} 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 in 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/554047v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1d949b5org.highwire.dtl.DTLVardef@7629ccorg.highwire.dtl.DTLVardef@1b2125dorg.highwire.dtl.DTLVardef@1d3cde1_HPS_FORMAT_FIGEXP M_FIG C_FIG