Icariin ameliorates glycolytic dysfunction in Alzheimer's disease models by activating the Wnt/β-catenin signaling pathway

• Published in: The FEBS journal Vol. 291; no. 10; pp. 2221 - 2241
• Main Authors: Liu, Ju, Wei, Ai-Hong, Liu, Ting-Ting, Ji, Xin-Hao, Zhang, Ying, Yan, Fei, Chen, Mei-Xiang, Hu, Jin-Bo, Zhou, Shao-Yu, Shi, Jing-Shan, Jin, Hai, Jin, Feng
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2024
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; beta Catenin - genetics; beta Catenin - metabolism; Catenin; Cell culture; Cell viability; Cognitive ability; Disease Models, Animal; Dkk1 protein; Flavonoids - pharmacology; Glycolysis; Glycolysis - drug effects; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; L-Lactate dehydrogenase; Lactate; Lactate dehydrogenase; Male; Mice; Mice, Transgenic; Neurodegenerative diseases; Neuroprotection; Neuroprotective Agents - pharmacology; Peptide Fragments - metabolism; Proteins; Signal transduction; Western blotting; Wnt protein; Wnt Signaling Pathway - drug effects; icariin; Wnt/β‐catenin signaling pathway; Alzheimer's disease; glycolysis; hexokinase
• DOI: 10.1111/febs.17099
• ISSN: 1742-464X; 1742-4658

It was reported that the Wnt/β-catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/β-catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg-AD mice were treated with ICA. HT22 cells, the Aβ peptide and Dickkopf-1 (DKK1) agent (a specific inhibitor of the Wnt/β-catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti-AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg-AD mice back to wild-type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aβ . However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg-AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/β-catenin pathway.