Binding of Cu2+ to Aβ1-29 causes aggregation and toxicity in SH-SY5Y cells
Binding of Cu2+ to Aβ1-29 causes aggregation and toxicity in SH-SY5Y cells
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Cu2+ 与 Aβ1-29 的结合导致 SH-SY5Y 细胞聚集和毒性
DOI：
10.1016/j.bbrc.2020.11.031
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发表时间：
2021
影响因子：
3.1
通讯作者：
Yamagishi Nobuyuki
中科院分区：
文献类型：
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作者：
Taniguchi Masanari;Saito Mayu;Kuga Takahisa;Yamagishi Nobuyuki
淀粉样蛋白(Aβ，Aβ)的积聚和聚集是阿尔茨海默病(AD)发病机制中的关键因素。一些研究表明，铜、锌等金属离子在神经毒性A-β聚集体的形成和稳定中起着关键作用，但A-β细胞毒性的分子机制尚未完全阐明。以前，我们发现Aβ衍生片段肽(Aβ-FrP)Aβ1-19在Cu2+存在的情况下改变构象，抑制其被金属蛋白酶-7(MMP7)消化。在本研究中，我们证明了Aβ1-19在Cu2+存在下不形成聚集体。因此，我们合成了一种新的Aβ-β1-29，它具有依赖于Cu2+的构象转化和聚集形成。Aβ1-29可被β-7切割，但在Cu2+存在下，该反应被抑制，其方式与A MMP1-19相似。有趣的是，AMMP1-29在锌离子存在下表现出构象转换和聚集体形成，但这并不能抵抗β-7的切割。此外，Aβ1-29在Cu2+存在的情况下可诱导神经细胞的凋亡，而在Cu2+存在的情况下无此作用。这些结果提示，与锌离子不同，铜离子可能在Aβ的聚集机制中发挥重要作用，从而在AD的病理过程中起重要作用。
The accumulation and aggregation of amyloid-β (Aβ) are critical factors in the pathogenesis of Alzheimer’s disease (AD). Several studies have indicated that metal ions such as Cu2+and Zn2+play a key role in the formation and stabilization of neurotoxic Aβ aggregates, however the molecular mechanisms underlying Aβ cytotoxicity have not yet been fully elucidated. Previously, we showed that the Aβ-derived fragment peptide (Aβ-FrP), Aβ1-19, altered conformation in the presence of Cu2+, inhibiting its digestion by metalloproteinase-7 (MMP-7). In this study we demonstrated that Aβ1-19 did not form aggregates in the presence of Cu2+. Therefore, we synthesized a new Aβ-FrP, Aβ1-29, which displayed Cu2+-dependent conformational conversion and aggregate formation. Aβ1-29 was cleaved by MMP-7, however this reaction was inhibited in the presence of Cu2+in a similar way to Aβ1-19. Interestingly, Aβ1-29 showed conformational conversion and aggregate formation in the presence of Zn2+, however this did not confer resistance against MMP-7 cleavage. Moreover, Aβ1-29 induced the apoptotic cell death of neural SH-SY5Y cells in the presence of Cu2+but not Zn2+. These results suggest that Cu2+, unlike Zn2+, may play an important role in the aggregation mechanism of Aβ and thus in the pathology of AD.