School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, PR China.
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, PR China; Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, N.T., Hong Kong SAR, PR China; Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, PR China.
J Ethnopharmacol. 2024 Jun 28;328:118113. doi: 10.1016/j.jep.2024.118113. Epub 2024 Mar 26.
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Tianma-Gouteng Pair (TGP), commonly prescribed as a pair-herbs, can be found in many Chinese medicine formulae to treat brain diseases. However, the neuroprotective effects and molecular mechanisms of TGP remained unexplored.
This study investigated the difference between the TgCRND8 and 5 × FAD transgenic mice, the anti-AD effects of TGP, and underlying molecular mechanisms of TGP against AD through the two mouse models.
Briefly, three-month-old TgCRND8 and 5 × FAD mice were orally administered with TGP for 4 and 6 months, respectively. Behavioral tests were carried out to determine the neuropsychological functions. Moreover, immunofluorescence and western blotting assays were undertaken to reveal the molecular mechanisms of TGP.
Although TgCRND8 and 5 × FAD mice had different beta-amyloid (Aβ) burdens, neuroinflammation status, and cognition impairments, TGP exerted neuroprotective effects against AD in the two models. In detail, behavioral tests revealed that TGP treatment markedly ameliorated the anxiety-like behavior, attenuated the recognition memory deficits, and increased the spatial learning ability as well as the reference memory of TgCRND8 and 5 × FAD mice. Moreover, TGP treatment could regulate the beta-amyloid precursor protein (APP) processing by inhibiting the Aβ production enzymes such as β- and γ-secretases and activating Aβ degrading enzyme to reduce Aβ accumulation. In addition, TGP reduced the Aβ level, the ratio of Aβ/Αβ, Aβ accumulation, and tau hyperphosphorylation in both the 5 × FAD and TgCRND8 mouse models. Furthermore, TGP ameliorated neuroinflammation by decreasing the densities of activated microglia and astrocytes, and inhibiting the production of inflammatory cytokines. TGP upregulated the SIRT1 and AMPK, and downregulated sterol response element binding protein 2 (SREBP2) in the brain of TgCRND8 mice and deactivation of the EPhA4 and c-Abl in the brain tissues of 5 × FAD mice.
Our experiments for the first time revealed the neuroprotective effects and molecular mechanism of TGP on 5 × FAD and TgCRND8 transgenic mouse models of different AD stages. TGP decreased the level of Aβ aggregates, improved the tauopathy, and reduced the neuroinflammation by regulation of the SIRT1/AMPK/SREBP2 axis and deactivation of EPhA4/c-Abl signaling pathway in the brains of TgCRND8 and 5 × FAD mice, respectively. All these findings unequivocally confirmed that the TGP would be promising in developing into an anti-AD therapeutic pharmaceutical.
阿尔茨海默病（AD）是一种进行性神经退行性疾病。天麻钩藤配对（TGP）通常作为一对草药使用，可在许多中药方剂中找到，用于治疗脑部疾病。然而，TGP 的神经保护作用及其分子机制仍未得到探索。
本研究通过两种小鼠模型，研究了 TgCRND8 和 5×FAD 转基因小鼠之间的差异、TGP 对 AD 的抗 AD 作用及其对 AD 的潜在分子机制。
简要地说，3 个月大的 TgCRND8 和 5×FAD 小鼠分别口服 TGP 4 个月和 6 个月。进行行为测试以确定神经心理功能。此外，进行免疫荧光和蛋白质印迹分析以揭示 TGP 的分子机制。
尽管 TgCRND8 和 5×FAD 小鼠的β淀粉样蛋白（Aβ）负担、神经炎症状态和认知障碍不同，但 TGP 对两种模型的 AD 均具有神经保护作用。具体而言，行为测试显示，TGP 治疗显著改善了 TgCRND8 和 5×FAD 小鼠的焦虑样行为，减轻了认知记忆缺陷，并提高了空间学习能力和参考记忆。此外，TGP 通过抑制 Aβ 产生酶（如β和γ-分泌酶）和激活 Aβ 降解酶来减少 Aβ 积累，从而调节β-淀粉样前体蛋白（APP）的处理。此外，TGP 降低了 Aβ 水平、Aβ/Αβ 比值、Aβ 积累和 tau 过度磷酸化在 5×FAD 和 TgCRND8 小鼠模型中。此外，TGP 通过降低活化小胶质细胞和星形胶质细胞的密度以及抑制炎性细胞因子的产生来改善神经炎症。TGP 上调了 SIRT1 和 AMPK，并下调了 TgCRND8 小鼠脑中的固醇反应元件结合蛋白 2（SREBP2），并在 5×FAD 小鼠脑组织中失活了 EphA4 和 c-Abl。
我们的实验首次揭示了 TGP 在不同 AD 阶段的 5×FAD 和 TgCRND8 转基因小鼠模型中的神经保护作用及其分子机制。TGP 通过调节 SIRT1/AMPK/SREBP2 轴和 EphA4/c-Abl 信号通路的失活，降低了 Aβ 聚集体的水平，改善了 tau 病，并减轻了 TgCRND8 和 5×FAD 小鼠大脑中的神经炎症。所有这些发现都明确证实，TGP 将有望开发成为一种抗 AD 治疗药物。
