Hopeahainol A attenuates memory deficits by targeting β‐amyloid in APP/PS1 transgenic mice

• Published in: Aging cell 2013-02, Vol.12 (1), p.85-92
• Main Authors: Zhu, Xiaolei, Ye, Lan, Ge, Huiming, Chen, Ling, Jiang, Nan, Qian, Lai, Li, Lingling, Liu, Rong, Ji, Shen, Zhang, Su, Jin, Jiali, Guan, Dening, Fang, Wei, Tan, Renxiang, Xu, Yun
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Aβ‐binding alcohol dehydrogenase; Brain - metabolism; Cells, Cultured; Female; Heterocyclic Compounds, 4 or More Rings - pharmacology; hopeahainol A; Humans; Male; Maze Learning - drug effects; Memory Disorders - drug therapy; Memory Disorders - genetics; Memory Disorders - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; neuroprotection; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - genetics; Peptide Fragments - metabolism; Presenilin-1 - genetics; Presenilin-1 - metabolism; β‐amyloid
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12022

Summary Increasing evidence demonstrates that amyloid beta (Aβ) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Aβ is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase‐inhibitory and anti‐oxidative in H2O2‐treated PC12 cells. In this study, we reported that HopA might bind to Aβ1–42 directly and inhibit the Aβ1–42 aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Aβ1–42 and Aβ‐binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long‐term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD.