越来越多的证据表明，健康饮食与阿尔茨海默病 (AD) 进展缓慢有关。类黄酮是对 AD 有益的饮食（例如地中海饮食）中最丰富的天然产物之一。然而，这些膳食黄酮类化合物对 AD 的作用和机制仍不完全清楚。在这里，我们发现代表性膳食天然黄酮类化合物白杨素 (Chr) 可显着改善 APP/PS1 小鼠的认知障碍和 AD 病理。此外，机制研究表明 Chr 显着降低淀粉样蛋白-β (Aβ) 和磷酸化 tau (p-tau) 的水平，并对 β 位点淀粉样蛋白前体蛋白裂解酶 1 (BACE1) 和糖原合酶激酶 3β 具有双重抑制活性（GSK3β）。此外，EW233 进一步证实了 Chr 的作用，EW233 是 Chr 的结构类似物，具有改善的药代动力学特征。为了进一步验证 Chr 和 EW233 的作用，我们利用之前建立的 AD 嵌合人脑类器官 (chCO) 模型，其中促进星形细胞生成以模拟人脑组织中的神经元-星形胶质细胞比例，以及类似的 Aβ 和 Aβ 双重抑制。还观察到p-tau。总而言之，我们的研究不仅揭示了膳食黄酮类化合物（例如 Chr）减轻 AD 病理的分子机制，而且还表明，识别模仿这些健康饮食的某些益处的特定成分可以作为发现新的有前途的方法。 AD 治疗。© 2024。作者获得 Springer Science Business Media, LLC（Springer Nature 的一部分）的独家许可。

Growing evidence indicates that healthy diets are associated with a slower progression of Alzheimer's disease (AD). Flavonoids are among the most abundant natural products in diets beneficial to AD, such as the Mediterranean diet. However, the effect and mechanism of these dietary flavonoids on AD remains incompletely understood. Here, we found that a representative dietary natural flavonoid, chrysin (Chr), significantly ameliorated cognitive impairment and AD pathology in APP/PS1 mice. Furthermore, mechanistic studies showed that Chr significantly reduced the levels of amyloid-β (Aβ) and phosphorylated tau (p-tau), along with dual inhibitory activity against β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase 3β (GSK3β). Moreover, the effect of Chr was further confirmed by EW233, a structural analog of Chr that exhibited an improved pharmacokinetic profile. To further verify the role of Chr and EW233, we utilized our previously established chimeric human cerebral organoid (chCO) model for AD, in which astrogenesis was promoted to mimic the neuron-astrocyte ratio in human brain tissue, and similar dual inhibition of Aβ and p-tau was also observed. Altogether, our study not only reveals the molecular mechanisms through which dietary flavonoids, such as Chr, mitigate AD pathology, but also suggests that identifying a specific constituent that mimics some of the benefits of these healthy diets could serve as a promising approach to discover new treatments for AD.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.