A novel rhamnoside derivative PL402 up-regulates matrix metalloproteinase 3/9 to promote Aβ degradation and alleviates Alzheimer's-like pathology.

Tingting Hu,Jing Lu,Yue Chen,Gang Pei,Xin Cao,Peng Xia,Yue Zhou

doi:10.18632/aging.102637

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

Alzheimer's disease (AD), the most common form of dementia [1], is a growing global health concern with huge influence for individuals and society [1,2,3]
All the results suggest that the designed rhamnoside derivatives, PL402 and PL201A, can reduce the Aβ level in vitro
We found that the new rhamnoside derivative named PL402 suppressed Aβ levels in various cell models, the expression or activity of β- and γ-secretases and amyloid precursor protein (APP) metabolism were not influenced by the PL402 treatment, suggesting the effect of rhamnoside derivatives on Aβ irrelevant of its generation

Summary

Introduction

Alzheimer's disease (AD), the most common form of dementia [1], is a growing global health concern with huge influence for individuals and society [1,2,3]. The Aβ peptide is sequentially cleaved from amyloid precursor protein (APP) by two proteinases, β-secretase (mainly BACE1) and γsecretase complex. The cleavage of APP by BACE1 generates an APP soluble fragment (sAPPβ) and a membrane-bound c-terminal fragment, which is further cleaved by a γ-secretase to produce the multiple Aβ peptides [12,13,14,15]. Accumulating evidence has indicated that impairment of Aβ clearance is a common overture to late-onset AD [19, 20] and several in vivo studies demonstrated that activation of ADEs prevented Aβ accumulation and AD pathology, suggesting that these ADEs could serve as the promising therapeutic targets for the treatment of AD [18, 21,22,23]

Methods

Results

Conclusion