Amyloid-β (Aβ) aggregated forms are highly associated with the onset of Alzheimer's disease (AD). Aβ abnormally accumulates in the brain and induces neuronal damages and symptoms of AD such as cognitive impairment and memory loss. Since an antibody drug, aducanumab, reduces Aβ aggregates and delays clinical decline, clearance of accumulated Aβ in the brain is accounted as a therapeutic approach to treat AD. In this study, we synthesized 17 benzofuran derivatives that may disaggregate Aβ oligomers and plaques into inert monomers. By a series of Aβ aggregation inhibition and aggregates' disaggregation assays utilizing thioflavin T assays and gel electrophoresis, YB-9, 2-((5-methoxy-3-(4-methoxyphenyl)benzofuran-6-yl)oxy)acetic acid, was selected as the final Aβ-disaggregator candidate. When it was orally administered to the 8-month-old male transgenic mouse model with five familial AD mutations (5XFAD) via drinking water daily for two months, Aβ oligomers and plaques in hippocampus were reduced. Consequently, decreased astrogliosis and rescued synaptic dysfunction were observed in the hippocampus of YB-9-treated 5XFAD mice compared with the untreated transgenic control group.
Keywords: 5XFAD mouse models; Alzheimer’s disease; amyloid-β aggregates; benzofuran derivatives; hippocampus; synapse.