Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 28; no. 1; pp. 11 - 20
• Main Authors: Li, Lin, Li, Wen-Jun, Zheng, Xiang-Ru, Liu, Qing-Long, Du, Qian, Lai, Yu-Jie, Liu, Song-Qing
• Format: Journal Article
• Language: English
• Published: London BioMed Central 29.01.2022; BMC
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - etiology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Animal cognition; Animals; Antibodies; Apoptosis; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cognition - drug effects; Disease Models, Animal; Disease Susceptibility; Eriodictyol; Female; Ferroptosis; Ferroptosis - drug effects; Flavanones - chemistry; Flavanones - pharmacology; Flavonoids; Immunohistochemistry; Mice; Mice, Transgenic; Molecular Medicine; NF-E2-Related Factor 2 - metabolism; Nrf2; Peptides; Phosphorylation; Protein Aggregation, Pathological; Reactive Oxygen Species - metabolism; Receptors, Calcitriol - metabolism; Research Article; Signal Transduction; tau Proteins - metabolism; Transgenic animals; VDR; Vitamin D; United States > US; China; Ferroptosis; Alzheimer’s disease; VDR; Nrf2; Eriodictyol
• ISSN: 1076-1551; 1528-3658; 1528-3658
• DOI: 10.1186/s10020-022-00442-3

Background Alzheimer’s disease (AD) is the most common type of neurodegenerative disease in the contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound that is mainly present in citrus fruits and some Chinese herbal medicines, has been reported to exert anti-inflammatory, antioxidant, anticancer and neuroprotective effects. However, few studies have examined the anti-AD effect and molecular mechanism of eriodictyol. Methods APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed using behavioral tests. The level of amyloid-β (Aβ) aggregation and hyperphosphorylation of Tau in the mouse brain were detected by preforming a histological analysis and Western blotting. HT-22 cells induced by amyloid-β peptide (1–42) (Aβ 1–42 ) oligomers were treated with eriodictyol, after which cell viability was determined and the production of p-Tau was tested using Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4 (GPX4), were determined both in vivo and in vitro using Fe straining, Western blotting and qPCR assays. Additionally, the expression level of vitamin D receptor (VDR) and the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested using Western blotting and qPCR assays. Afterward, HT-22 cells with VDR knockout were used to explore the potential mechanisms, and the relationship between VDR and Nrf2 was further assessed by performing a coimmunoprecipitation assay and bioinformatics analysis. Results Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, and suppressed Aβ aggregation and Tau phosphorylation in the brains of APP/PS1 mice. Moreover, eriodictyol inhibited Tau hyperphosphorylation and neurotoxicity in HT-22 cells induced by Aβ 1–42 oligomer. Furthermore, eriodictyol exerted an antiferroptosis effect both in vivo and in vitro, and its mechanism may be associated with the activation of the Nrf2/HO-1 signaling pathway. Additionally, further experiments explained that the activation of Nrf2/HO-1 signaling pathway by eriodictyol treatment mediated by VDR. Conclusions Eriodictyol alleviated memory impairment and AD-like pathological changes by activating the Nrf2/HO-1 signaling pathway through a mechanism mediated by VDR, which provides a new possibility for the treatment of AD.