Bibliographic
This study investigated effects of gamma secretase modulator CHF5074 on tau pathology in AD Tg mice. Past studies have shown CHF5074 reduced the brain plaque burden and attenuated memory deficit in different APP transgenic mouse models of AD. It is proposed that in the pathogenesis of AD, Aβ accumulation precedes tau hyperphosphorylation and both processes contribute to the cognitive decline, but the efficacy of γ-secretase modulators in modifying tau pathology is still poorly investigated. Among the kinases catalyzing tau phosphorylation, GSK-3β is mostly involved. Results in this study show CHF5074 was more effective than ibuprofen in reducing tau pathology, though both compounds decreased the GSK-3β level and increased the GSK-3β inhibitory phosphorylation near to the non-Tg values. The inhibition of GSK-3β appeared to be secondary to the reduction of Aβ generation as, differently from LiCl, CHF5074 reproduced its effect in hAPP overexpressing neuroglioma cells, but not in wildtype primary neurons. This study shows that the novel γ-secretase modulator CHF5074 can fully reverse β-amyloid associated tau pathology, thus representing a promising therapeutic agent for AD.