Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid,Inorganic Chemistry

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Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2018-05-18 00:00:00 , DOI: 10.1021/acs.inorgchem.8b00391
Mariusz Mital _{1,

2} , Wojciech Bal ₂ , Tomasz Frączyk _{2,

3} , Simon C. Drew ₄

Affiliation

Sporadic Alzheimer’s disease (AD) is associated with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. The protein levels and activity of the Zn²⁺-dependent endopeptidase neprilysin (NEP) inversely correlate with brain Aβ levels during aging and in AD. The present study considered the ability of Cu²⁺ ions to inhibit human recombinant NEP and the role for NEP in generating N-truncated Aβ fragments with high-affinity Cu²⁺ binding motifs that can prevent this inhibition. Divalent copper noncompetitively inhibited NEP (K_i = 1.0 μM), while proteolysis of Aβ yielded the soluble, Aβ_4–9 fragment that can bind Cu²⁺ with femtomolar affinity at pH 7.4. This provides Aβ_4–9 with the potential to act as a Cu²⁺ carrier and to mediate its own production by preventing NEP inhibition. Enzyme inhibition at high Zn²⁺ concentrations (K_i = 20 μM) further suggests a mechanism for modulating NEP activity, Aβ_4–9 production, and Cu²⁺ homeostasis.

中文翻译：

铜，脑啡肽酶和β淀粉样蛋白的N截短之间的相互作用

偶发性阿尔茨海默氏病（AD）与β-淀粉样蛋白（Aβ）肽从中枢神经系统清除不充分有关。Zn ²⁺依赖性内肽酶中性溶酶（NEP）的蛋白质水平和活性与衰老和AD中脑Aβ水平成反比。本研究考虑了Cu ²⁺离子抑制人重组NEP的能力以及NEP在产生具有高亲和力的Cu ²⁺结合基序可以阻止这种抑制作用的N截短的Aβ片段中的作用。二价铜非竞争性抑制NEP（K _i = 1.0μM），而Aβ的蛋白水解产生可与Cu ²⁺结合的可溶性_Aβ4–9片段在pH 7.4下具有飞摩尔亲和力。这提供了Aβ _4-9与充当铜的电位²⁺载体并且通过防止NEP抑制介导其自身的生产。酶抑制在高的Zn ²⁺浓度（ķ_我= 20μM）还建议用于调节NEP活性，Aβ的机构_4-9的生产，和Cu ²⁺动态平衡。

更新日期：2018-05-18

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