13th International Symposium on Pharmaceutical Sciences (ISOPS), Ankara, Turkey, 22 - 25 June 2021, pp.1-2
Introduction: Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles caused by abnormal phosphorylation of the microtubule-associated tau protein, amyloid plaques composed of β-amyloid peptide (Ab, 40-42 aa) derived by proteolytic cleavage of amyloid precursor protein (APP) and loss of cholinergic neurons. Currently, most of FDA-approved AD drugs available on the market are cholinesterase inhibitors (ChEIs) that target the cholinergic system. Although ChEIs provide symptomatic therapy, recent findings have shown that some ChEIs can also affect amyloid metabolism and/or tau phosphorylation (1). Recently, we have demonstrated that toluidine blue O (TBO), a phenothiazine-structured compound, is a potent inhibitor of acetylcholinesterase and butyrylcholinesterase (2) and also decreases extracellular Aβ40, Aβ42, sAPP expression in a dose-dependent manner in PS70 cells (3). Furthermore, our in vivo studies have shown that TBO reduces insoluble Aβ plaques while it does not affect tau pathology significantly at the selected treatment conditions in the hippocampus of 3xTgAD mice that mimic neuropathological features of AD (4). The aim of this study was to investigate whether TBO may affect tau pathology in N2a mouse neuroblastoma cells stably expressing the human Swedish mutant APP695 (N2a/APPSwe) cells.
Materials and Methods: N2a/APPSwe cells were treated with 0-5 mM TBO for 24 hours. After treatment, total tau levels were assessed by Western blot using HT7 antibody in cell lysates. Also the levels of tau phosphorylated at residues Thr181 and Ser202/Thr205 were detected using antibodies AT270 and AT8, respectively.
Results: Our findings demonstrated that TBO reduces the levels of total tau and phosphorylated tau at residues Thr181 and Ser202/Thr205 when compared to control.
Conclusions: Overall, our new data support the idea that TBO may be a promising drug candidate in the treatment of AD.
This study was supported by a grant from the Scientific Research Unit of Hacettepe University (HUBAB, TSA-2019-17288).