Identification of a dual Aβ‐tau disaggregator for the treatment of Alzheimer’s disease

Abstract

AbstractBackgroundThe accumulation of misfolded protein aggregates is connected with neurodegenerative diseases such as Alzheimer’s disease (AD), and Parkinson’s disease. Because of the accumulation of amyloid β (Aβ) plaques and tau tangles (NFTs) in the brain, neurons slowly degenerate and lose their functions in AD. Recently, many clinical trials for AD therapy with single‐target drugs, especially targeted for Aβ or tau aggregates, have failed. As a therapeutic strategy for AD, we therefore propose to introduce a multifunctional anti‐AD agent to disaggregate the Aβ plaques and NFTs.MethodHit compound was selected with disaggregation of Aβ and tau aggregates in various concentrations and half maximal effective concentration by thioflavin T (ThT) fluorescence assay. In vitro study, we examined the effects of our hit compound on the accumulation of intracellular Aβ or tau in over‐expressing cells. In vivo study, we administrated orally our hit compound to AD mouse model for 12 weeks (100mg/kg by weekly). Analysis of Aβ and tau was performed by molecular biological and histological experiments.ResultOur results show that the hit compound had dual disaggregation capacity for Aβ and tau aggregates. We observed significant decrease of Aβ and NFTs in hit compound treated AD mice compared to vehicle treated. Also, we found the restoration of cognitive decline in compound treated AD mice.ConclusionThe study demonstrate that our hit compound was identified as dual functional drug for Aβ and NFTs disaggregator. These findings may help to design the next generations of dual or selective disaggregators.