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首页> 外文期刊>Neuro-degenerative diseases >Destruxin E decreases Beta-amyloid generation by reducing colocalization of beta-amyloid-cleaving enzyme 1 and beta-amyloid protein precursor.
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Destruxin E decreases Beta-amyloid generation by reducing colocalization of beta-amyloid-cleaving enzyme 1 and beta-amyloid protein precursor.

机译：Destruxin E通过减少β-淀粉样蛋白裂解酶1和β-淀粉样蛋白前体的共定位作用来减少β-淀粉样蛋白的生成。

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摘要

Alzheimer-disease-associated beta-amyloid (Abeta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (betaAPP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces Abeta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce Abeta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces Abeta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and betaAPP, which reduces beta-cleavage of betaAPP. Therefore, the data demonstrate that Dx-E represents a novel Abeta-reducing process which could have fewer side effects than secretase inhibitors.
机译：阿尔茨海默氏病相关的β-淀粉样蛋白（Abeta）是通过β-淀粉样蛋白前体（betaAPP）的顺序内切水解产生的：胞外部分通过β-淀粉样蛋白裂解酶（BACE）/β-分泌酶，然后在跨膜结构域中间附近被早老素（PS）/γ-分泌酶切割。因此，抑制任何一种分泌酶都会减少Abeta的产生，并且是开发预防阿尔茨海默氏病的药物的基本策略。但是，尚不清楚在抑制分泌酶的情况下，小化合物如何减少Abeta的产生。预期此类化合物可避免分泌酶抑制剂的某些副作用。在这里，我们报告说，destruxin E（Dx-E），一种天然的环六肽，减少了Abeta的产生，而不影响BACE或PS /γ-分泌酶的活性。与此相符，Dx-E没有抑制Notch信号传导。我们发现Dx-E减少了BACE1和betaAPP的共定位，从而减少了betaAPP的beta切割。因此，数据证明Dx-E代表一种新颖的Abeta减少过程，其副作用可能少于分泌酶抑制剂。

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