The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aβ) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aβ and phospho-Tau in AD. Peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that can activate autophagy, and transcriptionally regulate transcription factor EB (TFEB) which is a key regulator of ALP. This suggests that targeting PPARα, to reduce ALP impairment, could be a viable strategy for AD therapy. In this study, we investigated the anti-AD activity of Caudatin, an active constituent of Cynanchum otophyllum (a traditional Chinese medicinal herb, Qing Yang Shen; QYS). We found that Caudatin can bind to PPARα as a ligand and augment the expression of ALP in microglial cells and in the brain of 3XTg-AD mice model. Moreover, Caudatin could activate PPARα and transcriptionally regulates TFEB-augmented lysosomal degradation of Aβ and phosphor-Tau aggregates in AD cell models. Oral administration of Caudatin decreased AD pathogenesis and ameliorated the cognitive dysfunction in 3XTg-AD mouse model. Conclusively, Caudatin can be a potential AD therapeutic agent via activation of PPARα-dependent ALP.

自噬-溶酶体途径 (ALP) 是参与阿尔茨海默病 (AD) 中聚集蛋白清除的主要细胞机制。然而，在 AD 发病过程中，ALP 由于有毒的β淀粉样蛋白 (Aβ) 和磷酸化 Tau (磷酸化 Tau) 蛋白在大脑中的积累而受到显着损害。因此，ALP 的激活可能会阻止 AD 中 Aβ 和磷酸 Tau 的产生增加。过氧化物酶体增殖物激活受体α（PPARα）是一种可以激活自噬的转录因子，并可转录调节转录因子EB（TFEB），而转录因子EB是ALP的关键调节因子。这表明针对 PPARα 来减少 ALP 损伤可能是 AD 治疗的可行策略。在本研究中，我们研究了 Caudatin 的抗 AD 活性， Caudatin 是徐长卿（一种传统中药清阳参；QYS）的活性成分。我们发现 Caudatin 可以作为配体与 PPARα 结合，并增强小胶质细胞和 3XTg-AD 小鼠模型大脑中 ALP 的表达。此外，Caudatin 可以激活 PPARα 并在转录上调节 AD 细胞模型中 TFEB 增强的 Aβ 和磷酸 Tau 聚集体的溶酶体降解。口服 Caudatin 可减少 3XTg-AD 小鼠模型中的 AD 发病机制并改善认知功能障碍。总之，Caudatin 可通过激活 PPARα 依赖性 ALP 成为潜在的 AD 治疗剂。