School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, People's Republic of China.
Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
J Neuroinflammation. 2023 Jan 30;20(1):19. doi: 10.1186/s12974-023-02704-1.
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba, exhibits multiple pharmacological properties, including neuroprotective effects. This study aimed to investigate the therapeutic effects of PA against AD using the TgCRND8 transgenic AD mouse model, and to explore the underlying mechanisms targeting CCAAT/enhancer-binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling pathway.
After genotyping to confirm the transgenicity, drug treatments were administered intragastrically once daily to 3-month-old TgCRND8 mice for 4 consecutive months. Several behavioral tests were applied to assess different aspects of neurological functions. Then the brain and colon tissues were harvested for in-depth mechanistic studies. To further verify whether PA exerts anti-AD effects via modulating C/EBPβ/AEP signaling pathway in TgCRND8 mice, adeno-associated virus (AAV) vectors encoding CEBP/β were bilaterally injected into the hippocampal CA1 region in TgCRND8 mice to overexpress C/EBPβ. Additionally, the fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of gut microbiota on the anti-AD effects of PA.
Our results showed that PA treatment significantly improved activities of daily living (ADL), ameliorated the anxiety-related behavioral deficits and cognitive impairments in TgCRND8 mice. PA modulated the amyloid precursor protein (APP) processing. PA also markedly reduced the levels of beta-amyloid (Aβ) and Aβ, suppressed Aβ plaque burdens, inhibited tau protein hyperphosphorylation at several sites and relieved neuroinflammation in the brains of TgCRND8 mice. Moreover, PA restored gut dysbiosis and inhibited the activation of the C/EBPβ/AEP signaling pathway in the brain and colon tissues of TgCRND8 mice. Interestingly, PA strikingly alleviated the AD-like pathologies induced by the overexpression of C/EBPβ in TgCRND8 mice. Additionally, the FMT of fecal microbiota from the PA-treated TgCRND8 mice significantly alleviated the cognitive impairments and AD-like pathologies in the germ-free TgCRND8 mice.
All these findings amply demonstrated that PA could ameliorate the cognitive deficits in TgCRND8 mice via suppressing Aβ plaques deposition, hyperphosphorylation of tau protein, neuroinflammation and gut dysbiosis through inhibiting the activation of C/EBPβ/AEP pathway, suggesting that PA is a promising naturally occurring chemical worthy of further development into the pharmaceutical treatment of AD.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，其特征是进行性认知功能障碍和行为障碍。广藿香醇（PA）从广藿香草中分离得到，具有多种药理作用，包括神经保护作用。本研究旨在使用 TgCRND8 转基因 AD 小鼠模型研究 PA 对 AD 的治疗作用，并探讨靶向 CCAAT/增强子结合蛋白β/天冬酰胺内肽酶（C/EBPβ/AEP）信号通路的潜在机制。
通过基因分型确认转基因后，将药物每天一次灌胃给药，连续 4 个月，给予 3 个月大的 TgCRND8 小鼠。应用多种行为测试评估神经功能的不同方面。然后采集大脑和结肠组织进行深入的机制研究。为了进一步验证 PA 是否通过调节 TgCRND8 小鼠中的 C/EBPβ/AEP 信号通路发挥抗 AD 作用，我们将编码 C/EBPβ 的腺相关病毒（AAV）载体双侧注射到 TgCRND8 小鼠的海马 CA1 区，以过表达 C/EBPβ。此外，进行粪便微生物群移植（FMT）实验以验证肠道微生物群对 PA 抗 AD 作用的潜在作用。
我们的结果表明，PA 治疗可显著改善 TgCRND8 小鼠的日常生活活动（ADL），改善焦虑相关的行为缺陷和认知障碍。PA 调节淀粉样前体蛋白（APP）的加工。PA 还显著降低β-淀粉样蛋白（Aβ）和 Aβ 的水平，抑制 TgCRND8 小鼠大脑中 tau 蛋白的多处磷酸化，并缓解神经炎症。此外，PA 恢复了 TgCRND8 小鼠的肠道菌群失调，并抑制了大脑和结肠组织中 C/EBPβ/AEP 信号通路的激活。有趣的是，PA 明显减轻了 TgCRND8 小鼠中 C/EBPβ 过表达引起的 AD 样病理。此外，来自 PA 治疗的 TgCRND8 小鼠的粪便微生物群的 FMT 可显著减轻无菌 TgCRND8 小鼠的认知障碍和 AD 样病理。
这些发现充分表明，PA 通过抑制 Aβ 斑块沉积、tau 蛋白过度磷酸化、神经炎症和肠道菌群失调，通过抑制 C/EBPβ/AEP 通路的激活来改善 TgCRND8 小鼠的认知缺陷，提示 PA 是一种有前途的天然化学物质，值得进一步开发为 AD 的药物治疗。
