Astaxanthin inhibits the aggregation and cytotoxicity of tau_4RDΔK280 via possible interaction with the aggregation-prone segments

Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau_4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau_4RDΔK280 cells while reducing the amount of tau_4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau_4RDΔK280 in vitro . Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau_4RDΔK280 in vitro . Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau_4RDΔK280 cells by preventing the formation of tau_4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau_4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.