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.
Highlights
This article has been corrected: The authors requested the replacement of panel C of Figure 3 because they reversed the inscriptions on this panel
N=4. (B–C) Representative image of a western blot showing the expression of MMP3 and MMP9 in SK-N-SH cells after treatment with vehicle (0.1% DMSO), or PL402 at 100μM and 300μM for 24h
N=4. (E) The levels of total Aβ produced by SK-N-SH cells measured by ELISA after treatment with vehicle (0.1% DMSO) or PL402 at 100μM and 300μM for 24 h in the cells infected with scrambled, MMP3 or MMP9 gene-specific shRNA
Summary
This article has been corrected: The authors requested the replacement of panel C of Figure 3 because they reversed the inscriptions on this panel. Correction for: A novel rhamnoside derivative PL402 up-regulates matrix metalloproteinase 3/9 to promote Aβ degradation and alleviates Alzheimer’s-like pathology
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