A novel compound RS-0466 reverses β-amyloid-induced cytotoxicity through the Akt signaling pathway in vitro

Abstract

β-Amyloid peptide is the principal protein in the senile plaques of Alzheimer's disease and is considered to be responsible for the pathology of Alzheimer's disease. Several studies have shown that β-amyloid is cytotoxic, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. Utilizing the MTT assay, we screened an in-house library to find compounds that suppress β-amyloid-induced inhibition of MTT reduction. From among the screening hits, we focused on 6-ethyl- N, N′-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), which had been newly synthesized in our laboratory. This compound was found to be capable of significantly inhibiting β-amyloid-induced cytotoxicity in HeLa cells and of reversing the decrease of phosphorylated Akt induced by β-amyloid. Furthermore, RS-0466 reversed the β-amyloid-induced impairment of long-term potentiation in rat hippocampal slices. These results raise the possibility that RS-0466 or its derivatives have potential as a therapeutic agent for Alzheimer's disease patients, and its effect is at least in part mediated by activation of Akt.