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首页> 美国卫生研究院文献>Aging (Albany NY) >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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A novel rhamnoside derivative PL402 up-regulates matrix metalloproteinase 3/9 to promote Aβ degradation and alleviates Alzheimer’s-like pathology

机译：一种新的犀牛衍生物PL402上调基质金属蛋白酶3/9以促进Aβ降解并减轻阿尔茨海默氏病病病理学

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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.
机译：淀粉样蛋白-β（Aβ）的积累被认为是阿尔茨海默病（AD）发病机制的主要原因，继承于其生物合成率和降解的速率。 Aβ降解是常见的序列对后期广告，靶向近年来β降解的损害。在这项研究中，我们证明了菌落苷衍生物PL402抑制了细胞模型中的Aβ水平而不改变与β生成相关的分泌酶的表达或活性。然而，属于淀粉样蛋白降解酶（AdES）的基质金属蛋白酶（MMP）3和9的水平由PL402上调。这两种酶的抑制或敲击废除了PL402的效果，表明PL402可以通过MMP3 / 9介导的Aβ劣化来降低Aβ。值得注意的是，PL402的给药在APP / PS1转基因小鼠中显着减弱了APP / PS1转基因小鼠的Aβ病理学和认知缺陷，其具有一致的Ades表达促进。因此，我们的研究表明，靶向Aβ降解可能是针对AD的有效策略，犀牛衍生物可能具有治疗效果。

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