posted on 2024-03-13, 12:47authored byJoanna
M. Wasielewska, Kathryn Szostak, Lachlan E. McInnes, Hazel Quek, Juliana C. S. Chaves, Jeffrey R. Liddell, Jari Koistinaho, Lotta E. Oikari, Paul S. Donnelly, Anthony R. White
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)
(CuII(atsm)) and a library of metal bis(thiosemicarbazone)
complexesa 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) (CuII(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 CuII(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.