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

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 potential. Mechanistically, SCL binds directly to CDK9, which contributes to the inflammatory response through its interaction with NF-κB. Knockdown of CDK9 reduced the NF-κB-mediated inflammatory response, but did not have an additive effect on SCL, indicating that SCL's efficacy is mediated by CDK9 inhibition and subsequent suppression of the NF-κB signaling pathway.

Conclusion

This study demonstrates that SCL exerts neuroprotective effects in AD mice by targeting CDK9 and downstream NF-κB signaling pathway to reduce the inflammatory activation of microglia. These findings suggest that SCL is a promising candidate for the treatment of AD, offering a novel therapeutic approach to mitigate disease progression through modulation of microglial activation.