Two 18‐norspirostane steroidal saponins as novel mitophagy enhancers improve Alzheimer's disease

作者：Wenqiao Qiu, Lu Yu, Changlong He, Jianming Wu, Betty Yuen Kwan Law, Chong‐Lin Yu, Dalian Qin, Xiaogang Zhou, Anguo Wu · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1390 · 被引用次数：20 · 研究领域：Alzheimer's disease research and treatments、14-3-3 protein interactions、Genomics, phytochemicals, and oxidative stress

The hallmark of Alzheimer's disease (AD) is the progressive accumulation of misfolded proteins, specifically beta-amyloid (Aβ) and Tau, leading to neurotoxicity and impaired neuronal function.1 Impaired mitophagy in AD contributes to protein buildup and subsequent neuronal damage.2 Mitophagy enhancers are investigated as potential therapeutic interventions for AD.3, 4 Deoxytrillenoside CA (DTCA) and epitrillenoside CA (ETCA), two newly discovered compounds derived from Trillium tschonoskii Maxim. (TTM) (Figure 1A), have shown antioxidative properties by inducing autophagy.5 Nevertheless, their impact on mitophagy induction and clearance of AD-related proteins remains unexplored. In this study, our primary focus was to investigate the autophagic degradation effects of DTCA&ETCA on AD-related proteins. To begin, the Aβ fibrillization was measured using the Thioflavin T (ThT) reagent. The results showed that DTCA&ETC, administrated at relatively safe concentrations (Figure S1), exhibited a dose-dependent reduction in ThT fluorescence, indicating the inhibition of Aβ1-42 (Figure 1B,C) and Aβ25-35 fibrilization (Figure S2A,B). The biolayer interferometry (BLI) analysis displayed that DTCA&ETCA directly bound to Aβ1-42 (Figure 1D,E). Subsequently, the effect of DTCA&ETCA on Aβ’s cytotoxicity was examined, revealing an increase in cell viability and a decrease in cell death and apoptosis of a immortalized mouse hippocampal neuronal cell line (HT-22) or a rat adrenal pheochromocytoma...