METHODS AND RESULTS: We investigated the effects of THICAPA on the amyloid precursor protein (APP) processing pathway in fibroblasts derived from patients with fAD. The in vitro cytotoxicity assay revealed no significant THICAPA cytotoxicity in fAD (AG06840) or healthy fibroblast cell lines (GM05879). Aβ scavenging assay revealed that 50 µM THICAPA potentially scavenged aged Aβ42 oligomers in the healthy fibroblast line. Gene and protein expression analyses revealed reduced APP expression and mature/immature APP expression ratio, BACE1 and presenilin 1 downregulation, and ADAM10 upregulation. Protein quantification revealed a significant reduction in C-terminal fragment beta, soluble APP (sAPP)β, and Aβ42/40 ratio in the amyloidogenic pathway and elevated sAPPα in the non-amyloidogenic pathway. Moreover, reactive oxygen species detection indicated that THICAPA reduced ROS production in fibroblasts from patients with fAD by 41.63%, although its intrinsic antioxidant properties were modest.
CONCLUSIONS: THICAPA attenuates amyloidogenesis and upregulates the non-amyloidogenic pathway while alleviating ROS production. These findings suggest that THICAPA is a potential therapeutic candidate for treating fAD.