Fenotiyazin Yapılı Bileşiklerin Amiloid Prekürsör Protein ve Amiloid Beta Peptitler Üzerindeki Etkilerinin Araştırılması

Abstract

In the present study, we aimed to investigate the effects of two phenothiazine-structured compounds [toluidine blue O (TBO) and thionine (TH)], which were found to be potent inhibitors of human erythrocyte acetylcholinesterase and human plasma butyrylcholinesterase in our previous studies, on the neuropathological hallmarks of Alzheimer’s disease (AD) in Chinese hamster ovary cells stably expressing human APP 751 and presenilin 1 (PS70) and in 3xTg-AD transgenic mice by using sandwich ELISA and Western blotting. After treatment of PS70 cells with 0-15 µM of TBO or TH, the levels of secreted Aβ40, Aβ42 and sAPPα were decreased in a dose-dependent manner compared with control. The effect of TBO on Aβ peptides was thought to be due to the lowered expression of amyloid precursor protein (APP) and β-site APP-cleaving enzyme 1 (BACE1) whereas TH reduced only APP expression. 3xTg-AD mice exhibiting age-dependent neuropathological characteristics of AD were separated into two groups as young and old mice, and those mice were intraperitoneally injected with 4 mg/kg phenothiazine-structured compound daily for 30 days. TH was found to have no effect on APP processing in young 3xTg-AD mice while TBO decreased the levels of insoluble Aβ peptides in the hippocampi of both young and aged mice. Besides, TBO administration did not cause any significant changes in the expression levels of APP, BACE1 and presenilin 1 in addition to tau hyperphoshorylation. Considering these findings, it was concluded that especially TBO might be a potential AD drug candidate and a better treatment in mild AD because of its inhibitory roles on cholinergic system and APP processing.