DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA | Aβ42 | GenicBio

Amyloid-β (Aβ) oligomers play a central role in Alzheimer’s disease (AD). Plaques of AD patients consist of Aβ40 and Aβ42 peptides and truncated Aβ peptides. The Aβ24 peptide, identified in human AD brains, was found to impair Aβ42 clearance through the brain–blood barrier. The Aβ24 peptide was also shown to reduce Aβ42 aggregation kinetics in pure buffer, but the underlying mechanism is unknown at atomistic level. In this study, we explored the conformational ensemble of the equimolar mixture of Aβ24 and Aβ42 by replica exchange molecular dynamics simulations and compared it to our previous results on the pure Aβ42 dimer. Our simulations demonstrate that the truncation at residue 24 changes the secondary, tertiary, and quaternary structures of the dimer, offering an explanation of the slower aggregation kinetics of the mixture.

淀粉样蛋白-β（Aβ）低聚物在阿尔茨海默病（AD）中起着核心作用。AD患者的斑块由Aβ40和Aβ42肽以及截短的Aβ肽组成。在人类AD大脑中鉴定的Aβ24肽被发现会损害Aβ42通过脑-血屏障的清除。Aβ24肽也被证明可以降低Aβ42在纯缓冲液中的聚集动力学，但其潜在机制在原子水平上尚不清楚。在本研究中，我们通过复制交换分子动力学模拟探索了Aβ24和Aβ42等摩尔混合物的构象系综，并将其与我们之前对纯Aβ42二聚体的结果进行了比较。我们的模拟表明，残基24处的截短改变了二聚体的二级、三级和四级结构，从而解释了混合物较慢的聚集动力学。

Formation of polymorphic amyloid fibrils is a common feature in neurodegenerative diseases involving protein aggregation. In Alzheimer’s disease, different fibril structures may be associated with different clinical sub-types. Structural basis of fibril polymorphism is thus important for understanding the role of amyloid fibrils in the pathogenesis and progression of these diseases. Here we studied two types of Aβ42 fibrils prepared under quiescent and agitated conditions. Quiescent Aβ42 fibrils adopt a long and twisted morphology, while agitated fibrils are short and straight, forming large bundles via lateral association. EPR studies of these two types of Aβ42 fibrils show that the secondary structure is similar in both fibril polymorphs. At the same time, agitated Aβ42 fibrils show stronger interactions between spin labels across the full range of the Aβ42 sequence, suggesting a more tightly packed structure. Our data suggest that cross-strand side chain packing interactions within the same β-sheet may play a critical role in the formation of polymorphic fibrils.

多态性淀粉样蛋白原纤维的形成是涉及蛋白质聚集的神经退行性疾病的常见特征。在阿尔茨海默病中，不同的原纤维结构可能与不同的临床亚型有关。因此，原纤维多态性的结构基础对于理解淀粉样原纤维在这些疾病的发病机制和进展中的作用很重要。在这里，我们研究了在静止和搅拌条件下制备的两种类型的Aβ42原纤维。静止的Aβ42原纤维采用长而扭曲的形态，而搅拌的原纤维短而直，通过横向缔合形成大束。对这两种类型的Aβ42原纤维的EPR研究表明，两种原纤维多晶型的二级结构相似。同时，在Aβ42序列的整个范围内，搅拌的Aβ42原纤维显示出自旋标记物之间更强的相互作用，表明其结构更加紧密。我们的数据表明，同一β-片内的跨链侧链堆积相互作用可能在多态原纤维的形成中发挥关键作用。

Aβ42序列分析：

引用文献：

1，Polymorphic Aβ42 fibrils adopt similar secondary structure but differ in cross-strand side chain stacking interactions within the same β-sheet

Hongsu Wang
Lan Duo,
Frederick Hsu,
Christine Xue,
Yoon Kyung Lee
…
Zhefeng Guo 
Scientific Reports volume 10, Article number: 5720 (2020)

2，Insights into the Mixture of Aβ24 and Aβ42 Peptides from Atomistic Simulations
Phuong H. Nguyen and Philippe Derreumaux
J. Phys. Chem. B 2022, 126, 50, 10689–10696

产品链接：http://www.genicbio.cn/detail.html?article_id=88

 

上海捷妮泰生物科技有限公司(GenicBio Limited)
微 信: 199 1653 7972
Q  Q: 1704635669
邮 箱: service@genicbio.cn
网 址: www.genicbio.cn