Title: Toluidine blue O modifies hippocampal amyloid pathology in a transgenic mouse model of Alzheimer's disease Yuksel M, Biberoglu K, Onder S, Akbulut KG, Tacal O Ref: Biochimie, 146:105, 2018 : PubMed
Recently, we have demonstrated that toluidine blue O (TBO), a phenothiazine dye, shows inhibitory effects on both cholinesterases and amyloid pathology in Alzheimer's disease (AD) cellular model. In the present study, we aimed to determine the effects of TBO (in a purity of 85%) on amyloid and tau pathologies in a triple transgenic mouse model of AD (3xTg-AD). Beginning at 7.5 (mild pathology) or 13 (severe pathology) months of age, 3xTg-AD mice were treated intraperitoneally with 4mg/kg TBO or vehicle daily for 30 days. TBO treatment significantly reduced the levels of insoluble Abeta40 and Abeta42 in the hippocampi of mild and severe pathology groups compared to vehicle-treated counterparts. When the levels of full-length amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1) were assessed in 3xTg-AD mice at late pathological stage, no significant changes were observed after TBO treatment. Similarly, TBO did not recover hyperphosphorylation of tau at residues Thr181 and Ser202/Thr205 significantly in soluble and insoluble hippocampal fractions of 3xTg-AD mice. Taken together, the current study is the first in vivo report, to our knowledge, demonstrating that TBO mitigates amyloid pathology in 3xTg-AD mice with no apparent change on tau phosphorylation. Overall, the preliminary data presented here support the possible use of TBO as a disease-modifying drug for AD treatment.
Title: Effects of phenothiazine-structured compounds on APP processing in Alzheimer's disease cellular model Yuksel M, Biberoglu K, Onder S, Akbulut KG, Tacal O Ref: Biochimie, 138:82, 2017 : PubMed
The excess accumulation of amyloid-beta (Abeta) peptides derived from the sequential cleavage of amyloid precursor protein (APP) by secretases, is one of the toxic key events leading to neuronal loss in Alzheimer's disease (AD). Studies have shown that cholinergic activity may also be involved in the regulation of APP metabolism. In the current study, we have investigated the roles of toluidine blue O (TBO) and thionine (TH), newly recognized phenothiazine-derived cholinesterase inhibitors, on the metabolism of APP in Chinese hamster ovary cells stably expressing human APP751 and presenilin 1 (PS70 cells). We assessed the effects of both compounds on the levels of Abeta, soluble APP-alpha (sAPPalpha), intracellular APP and beta-site APP-cleaving enzyme 1 (BACE1). After treatment of PS70 cells with TBO or TH without any side effect on cell viability, the levels of secreted Abeta40, Abeta42 and sAPPalpha were assayed by specific sandwich ELISAs while APP and BACE1 in cell lysates were analyzed using Western blot. The secreted Abeta40, Abeta42 and sAPPalpha in TBO- and TH-treated cells were found to be reduced in a dose-dependent manner compared to vehicle-treated cells. Results suggest that TH mitigated the Abeta pathology by lowering APP levels whereas reduced Abeta caused by TBO treatment seems to be the outcome of both less substrate availability and amyloidogenic APP processing. Taken together, our results represent the first report demonstrating that TBO and TH can affect amyloid metabolism in vitro.
