School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
J Biochem Mol Toxicol. 2019 Nov;33(11):e22395. doi: 10.1002/jbt.22395. Epub 2019 Oct 4.
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 Aβ aggregation and destabilizes preformed Aβ fibrils through directly interacting with the N-terminus and middle domains of Aβ peptides. Consequently, raloxifene not only reduces direct toxicity of Aβ in HT22 neuronal cells, but also suppresses expressions of tumor necrosis factor-α and transforming growth factor-β induced by Aβ peptides, and then alleviates microglia-mediated indirect toxicity of Aβ to HT22 neuronal cells. Our results suggested an alternative possible explanation for the neuroprotective activity of raloxifene in AD prevention.
雷洛昔芬是一种选择性雌激素受体调节剂，对预防绝经后妇女的阿尔茨海默病（AD）具有益处，因为绝经期间的激素变化有可能影响 AD 的发病机制，但它的神经保护作用的潜在机制尚不完全清楚。在这项研究中，评估了雷洛昔芬对淀粉样蛋白-β（Aβ）淀粉样生成的影响。结果表明，雷洛昔芬通过与 Aβ 肽的 N 端和中间结构域直接相互作用，抑制 Aβ 聚集并使已形成的 Aβ 纤维不稳定。因此，雷洛昔芬不仅降低了 Aβ 在 HT22 神经元细胞中的直接毒性，还抑制了 Aβ 肽诱导的肿瘤坏死因子-α和转化生长因子-β的表达，从而减轻了 Aβ 对 HT22 神经元细胞的小胶质细胞介导的间接毒性。我们的研究结果为雷洛昔芬在预防 AD 中的神经保护活性提供了另一种可能的解释。
