Osmundacetone ameliorates Alzheimer's-like pathologies by inhibiting β-amyloid fibrillation, oxidative damage and neuroinflammation in APP/PS1 transgenic mice

• Published in: Phytomedicine (Stuttgart) Vol. 135; p. 156091
• Main Authors: Zhao, Ling-Xiao, Ren, Hang, Su, Jing-Yang, Zhang, Qi, He, Da-Long, Wu, Ting-Yao, Zhang, Yan-Hui, Wang, Zhan-You, Fan, Yong-Gang
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.12.2024
• Subjects: Alzheimer's disease; Neuroinflammation; Osmundacetone; Oxidative damage; β-amyloid; APP; BBB; DMSO; NF-kB; TREM2; IDE; PS2; PS1; IFN-α; Aβ; IFN-β; LAMP1; FBS; LAMP2; ITDRF–CETSA; SCD1; Alzheimer's disease; β-amyloid; AD; iMScope; GPX4; EGCG; ADAM10; SYP; IL-1β; MMP9; Osmundacetone; BACE1; OAC; sAPPα; NeuN; sAPPβ; OABL; TCM; ThT; LRP1; AFM; Iba1; NMDAR2A; FOXO1; PDB; CETSA; Nrf2; NLRP3; 8-OHdG; ATP6V0A1; AβO; MOE; MWM; Oxidative damage; cPLA2; Neuroinflammation; RAGE; SOD2; CQ; NFTs; PSD95; TNF-α; APP/PS1; NOX4
• ISSN: 0944-7113; 1618-095X; 1618-095X
• DOI: 10.1016/j.phymed.2024.156091

•Osmundacetone (OAC) directly binds to Aβ and inhibits their fibrillation.•Binding of Aβ with OAC promotes its own lysosomal degradation.•OAC restores the Aβ-induced oxidative/inflammatory imbalance and prevents synaptic loss. β-Amyloid (Aβ) fibrillation is critical for Aβ deposition and cytotoxicity during the progression of Alzheimer's disease (AD). Consequently, anti-Aβ monoclonal antibody drugs targeting Aβ oligomers and aggregation are considered potential therapeutic strategies for AD treatment. Similar to the working mechanisms of anti-Aβ monoclonal antibody drugs, our study identified osmundacetone (OAC), a small-molecule compound isolated from the traditional Chinese medicine Rhizoma Osmundae, as exerting anti-AD effects by targeting Aβ. This study sought to determine whether OAC influences the Aβ burden in APP/PS1 mice and to identify potential regulatory mechanisms. Five-month-old APP/PS1 mice were injected intraperitoneally with OAC at a dose of 1 mg/kg for 12 weeks. The cognitive functions of the mice were assessed via the Morris water maze test and the open field test. Osmundacetone was analyzed via molecular docking, an isothermal dose‒response fingerprint-cellular context thermal shift assay, a thioflavine T fluorescence assay, and an atomic force microscopy assay to analyze the effects of OAC on Aβ fibrillation. Immunofluorescence, immunoblotting, and immunohistochemistry were used to assess Aβ clearance, AD pathology, oxidative stress, and inflammatory responses. The innovative biochemical and physical data illustrated that the ability of OAC to inhibit Aβ fibrillation was accomplished by binding directly to Aβ, which differed from the majority of previously reported natural polyphenols that modulate the Aβ content and structure in an indirect manner. The inhibition of Aβ fibrosis by OAC subsequently promoted Aβ lysosomal degradation, resulting in a decreased Aβ burden in APP/PS1 mice. Furthermore, OAC treatment inhibited oxidative damage by upregulating glutathione peroxidase expression and attenuated the production of inflammatory factors by downregulating nuclear factor-kB phosphorylation in APP/PS1 mice. These findings demonstrate, for the first time, that OAC could reduce the brain Aβ burden in APP/PS1 mice by inhibiting Aβ fibrillation through direct binding to Aβ and improve cognitive dysfunction by attenuating oxidative damage and neuroinflammation. These findings indicate that OAC may be a promising candidate for the treatment of AD. Pattern diagram of OAC inhibiting Alzheimer's-like neuropathy. OAC inhibits Alzheimer's-like pathologies through multiple mechanisms as follows: (1) inhibiting Aβ deposition via directly binding to Aβ to block the Aβ fibrillation process; (2) reducing Aβ content via promoting lysosomal degradation of Aβ by binding to Aβ; (3) alleviating neuroinflammation via inhibiting p-NF-κB expression; (4) repressing oxidative stress via upregulating GPX4 expression. [Display omitted]