2. Academic Validation
  3. Dietary Flavonoid Chrysin Functions as a Dual Modulator to Attenuate Amyloid-β and Tau Pathology in the Models of Alzheimer's Disease

Dietary Flavonoid Chrysin Functions as a Dual Modulator to Attenuate Amyloid-β and Tau Pathology in the Models of Alzheimer's Disease

  • Mol Neurobiol. 2024 Oct 21. doi: 10.1007/s12035-024-04557-y.
Zhen Zhang # 1,  Rongyao Li # 1,  Yue Zhou 1,  Shichao Huang 1,  Yujun Hou 2,  Gang Pei 3 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Shanghai East Hospital, Tongji University, Shanghai, China.
  • 3 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China. gpei@sibs.ac.cn.
  • 4 Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, China. gpei@sibs.ac.cn.
  • 5 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. gpei@sibs.ac.cn.
  • # Contributed equally.
PMID: 39432184 DOI: 10.1007/s12035-024-04557-y
Abstract

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.

Keywords

Alzheimer’s disease; Amyloid-β and tau pathology; Dietary chrysin; Human cerebral organoid.

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