Sclareol improves the pathology of Alzheimer's disease by inhibiting microglial inflammation via interacting with CDK9.

作者：Hao Tang, Luyao Li, Qin Yu, Linjie Chen, Xiaoxia Xu, Ziyao Meng, Yuqing Zeng, Fan Chen, Hammad Muzaffar, Wei Wang, Xia Zhao, Guang Liang · 发表于：Phytomedicine · 年份：2025 · DOI：10.1016/j.phymed.2025.156504 · 被引用次数：9 · 研究领域：Medicine

BACKGROUND Excessive activation of microglia triggers pro-inflammatory responses, exacerbating neuronal damage and accelerating the progression of Alzheimer's disease (AD). Thus, targeting abnormal microglial activation represents a promising therapeutic strategy for AD. In this study, we identified sclareol (SCL) through compound library screening as a potent anti-inflammatory agent capable of crossing the blood-brain barrier. However, there are currently no reports on whether SCL modulates microglial inflammation or ameliorates AD pathology. OBJECTIVE To evaluate the anti-inflammatory effects and underlying molecular mechanism of SCL on microglial-mediated inflammation and neuronal damage in AD. METHODS Drug Affinity Responsive Target Stability (DARTS), Liquid Chromatography-Tandem Mass Spectrometry (LC-MS), protein interaction assays, Biolayer Interferometry (BLI), and molecular docking were used to explore the interaction between SCL and cyclin-dependent kinase 9 (CDK9). Behavioral tests and immunofluorescent (IF) staining were performed to assess the effects of SCL on microglial activation and AD pathology. The molecular mechanism of the anti-inflammatory effect of SCL was analyzed by interfering with CDK9. RESULTS SCL significantly inhibited the release of proinflammatory mediators, reduced neuronal damage, and alleviated cognitive deficits in AD model mice. Notably, SCL demonstrated the ability to cross the blood-brain barrier (BBB), highlighting its therapeutic ...