低密度脂蛋白胆固醇和内溶酶体在淀粉样蛋白形成和阿尔茨海默病中的作用。

Xuesong Chen, Liang Hui, Jonathan D Geiger
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引用次数: 25

摘要

迟发性散发性阿尔茨海默病(AD)的发病机制被认为是营养、环境、表观遗传和遗传因素复杂相互作用的结果。在这些因素中,与APOE基因型无关的循环胆固醇稳态的改变继续与β淀粉样蛋白(Aβ)的脑沉积和AD的发病机制有关。人们认为,淀粉样蛋白β前体蛋白(a - β pp)进入内溶酶体似乎在a - β pp的淀粉样变性过程中起着关键作用,因为这正是a - β pp代谢中至关重要的两种酶所在的位置;淀粉样蛋白转化酶(BACE-1)和分泌酶。我们的研究表明,低密度脂蛋白胆固醇水平升高可促进Aβ pp内化,扰乱神经元内溶酶体的结构和功能,增加神经元内溶酶体中Aβ的积累。在这里,我们将进一步讨论LDL胆固醇水平升高与AD发病机制之间的联系,并探讨血浆LDL胆固醇水平升高促进淀粉样蛋白形成的潜在机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Role of LDL cholesterol and endolysosomes in amyloidogenesis and Alzheimer's disease.

The pathogenesis of late-onset sporadic Alzheimer's disease (AD) is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, altered circulating cholesterol homeostasis, independent of the APOE genotype, continues to be implicated in brain deposition of amyloid beta protein (Aβ) and the pathogenesis of AD. It is believed that trafficking of amyloid beta precursor protein (AβPP) into endolysosomes appears to play a critical role in determining amyloidogenic processing of AβPP because this is precisely where two enzymes critically important in AβPP metabolism are located; beta amyloid converting enzyme (BACE-1) and gamma secretase enzyme. We have shown that elevated levels of LDL cholesterol promote AβPP internalization, disturb neuronal endolysosome structure and function, and increase Aβ accumulation in neuronal endolysosomes. Here, we will further discuss the linkage between elevated levels of LDL cholesterol and AD pathogenesis, and explore the underlying mechanisms whereby elevated levels of plasma LDL cholesterol promote amyloidogenesis.

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