Raloxifene alleviates amyloid‐β‐induced cytotoxicity in HT22 neuronal cells via inhibiting oligomeric and fibrillar species formation

: Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-β (Aβ) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aβ42 aggregation and destabilizes preformed Aβ42 fibrils through directly interacting with the N-terminus and middle domains of Aβ42 peptides. Consequently, raloxifene not only reduces direct toxicity of Aβ42 in HT22 neuronal cells, but also suppresses expressions of tumor necrosis factor-α and transforming growth factor-β induced by Aβ42 peptides, and then alleviates microglia-mediated indirect toxicity of Aβ42 to HT22 neuronal cells. Our results suggested an alternative possible explanation for the neuroprotective activity of raloxifene in AD prevention.