Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China.
Phytomedicine. 2024 Dec;135:156091. doi: 10.1016/j.phymed.2024.156091. Epub 2024 Sep 21.
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.
β-淀粉样蛋白（Aβ）纤维形成对于阿尔茨海默病（AD）进展过程中 Aβ的沉积和细胞毒性至关重要。因此，靶向 Aβ寡聚物和聚集的抗 Aβ单克隆抗体药物被认为是 AD 治疗的潜在治疗策略。与抗 Aβ单克隆抗体药物的作用机制类似，我们的研究发现，从中药菝葜中分离得到的小分子化合物 osmundacetone（OAC）通过靶向 Aβ发挥抗 AD 作用。
本研究旨在确定 OAC 是否影响 APP/PS1 小鼠的 Aβ负担，并确定潜在的调节机制。
将 5 月龄的 APP/PS1 小鼠腹腔注射 OAC（剂量为 1mg/kg），共 12 周。通过 Morris 水迷宫试验和旷场试验评估小鼠的认知功能。采用分子对接、等温剂量反应指纹-细胞环境热位移测定、硫代黄素 T 荧光测定和原子力显微镜测定分析 OAC 对 Aβ纤维形成的影响。采用免疫荧光、免疫印迹和免疫组织化学分析评估 Aβ清除、AD 病理学、氧化应激和炎症反应。
创新的生化和物理数据表明，OAC 抑制 Aβ纤维形成的能力是通过直接与 Aβ结合来实现的，这与大多数先前报道的天然多酚不同，后者以间接方式调节 Aβ的含量和结构。OAC 抑制 Aβ纤维化后促进 Aβ溶酶体降解，从而降低 APP/PS1 小鼠的 Aβ负担。此外，OAC 治疗通过上调谷胱甘肽过氧化物酶的表达抑制氧化损伤，并通过下调 APP/PS1 小鼠核因子-κB 磷酸化来减轻炎症因子的产生，从而改善认知功能障碍。
这些发现首次表明，OAC 可以通过直接与 Aβ结合抑制 Aβ纤维形成，从而减少 APP/PS1 小鼠脑内 Aβ的负担，并通过减轻氧化损伤和神经炎症改善认知功能障碍。这些发现表明，OAC 可能是治疗 AD 的一种有前途的候选药物。
