Research Paper Volume 12, Issue 1 pp 481—501
A novel rhamnoside derivative PL402 up-regulates matrix metalloproteinase 3/9 to promote Aβ degradation and alleviates Alzheimer’s-like pathology
- 1 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- 2 Shanghai EW Medicine Co. Ltd, Shanghai 201203, China
- 3 Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai 200032, China
- 4 Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
Received: June 27, 2019 Accepted: December 23, 2019 Published: January 5, 2020
https://doi.org/10.18632/aging.102637How to Cite
Abstract
The accumulation of amyloid-β (Aβ), considered as the major cause of Alzheimer’s disease (AD) pathogenesis, relays on the rate of its biosynthesis and degradation. Aβ degradation is a common overture to late-onset AD and targeting the impairment of Aβ degradation has gained attention in the recent years. In this study, we demonstrated a rhamnoside derivative PL402 suppressed Aβ level in cell models without changing the expression or activity of Aβ generation-related secretases. However, the levels of matrix metalloproteinase (MMP) 3 and 9, belonging to amyloid-degrading enzymes (ADEs), were up-regulated by PL402. The inhibition or the knockdown of these two enzymes abolished the effect of PL402, indicating that PL402 may reduce Aβ via MMP3/9-mediated Aβ degradation. Notably, administration of PL402 significantly attenuated Aβ pathology and cognitive defects in APP/PS1 transgenic mice with the consistent promotion of ADEs expression. Thus, our study suggests that targeting Aβ degradation could be an effective strategy against AD and the rhamnoside derivatives may have therapeutic effects.