Department of Pharmacy, Xuanwu Hospital of Capital, Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun St, Xicheng District, Beijing 100053, P. R. China.
Am J Chin Med. 2022;50(6):1599-1615. doi: 10.1142/S0192415X22500677. Epub 2022 Jul 2.
Improving autophagy-lysosome fusion has been considered a key method in the treatment of Alzheimer's disease (AD). Cornel iridoid glycoside (CIG) is extracted from and has been shown to promote the clearance of tau oligomers via the autophagy pathway. However, the mechanisms of CIG on autophagy deficits are not understood. Here, we found autophagy deficit and tau aggregation in the brains of P301S tau transgenic mice and MAPT cells edited using CRISPR-Cas9 technology. CIG decreased tau aggregation and alleviated autophagic markers involving the JNK/Beclin-1 signaling pathway which demonstrated CIG that might enhance lysosome formation by upregulating ATPase Vps4A expression. Knocking down VPS4A increased autophagosome accumulation and attenuated the effect of CIG on p62. In addition, CIG had no effect on tau oligomers but still inhibited the level of tau monomer in VPS4A knockout cells. The effective component (Sweroside, SWE) of CIG attenuated tau oligomers accumulation and increased Vps4A level but not CHMP2B. SWE could not change the level of tau oligomers in VPS4A knockout cells. In conclusion, CIG suppressed autophagosome accumulation by regulating the ATPase Vps4A/JNK. SWE is a core of active factors of CIG in Vps4A regulation. These findings suggest CIG may be a potential drug in AD treatment.
促进自噬-溶酶体融合已被认为是治疗阿尔茨海默病 (AD) 的关键方法。Cornel 裂环环烯醚萜苷 (CIG) 从 中提取，已被证明可通过自噬途径促进 tau 寡聚物的清除。然而，CIG 对自噬缺陷的机制尚不清楚。在这里，我们发现在 P301S tau 转基因小鼠和使用 CRISPR-Cas9 技术编辑的 MAPT 细胞中存在自噬缺陷和 tau 聚集。CIG 减少 tau 聚集并减轻涉及 JNK/Beclin-1 信号通路的自噬标志物，表明 CIG 可能通过上调 ATPase Vps4A 表达增强溶酶体形成。敲低 VPS4A 会增加自噬体的积累，并减弱 CIG 对 p62 的作用。此外，CIG 对 tau 寡聚物没有影响，但仍能抑制 VPS4A 敲除细胞中 tau 单体的水平。CIG 的有效成分（梓醇，SWE）可减轻 tau 寡聚物的积累并增加 Vps4A 水平，但不增加 CHMP2B。SWE 不能改变 VPS4A 敲除细胞中 tau 寡聚物的水平。总之，CIG 通过调节 ATPase Vps4A/JNK 来抑制自噬体的积累。SWE 是 CIG 在 Vps4A 调节中的活性成分核心。这些发现表明 CIG 可能是 AD 治疗的一种潜在药物。
