Amylin-Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease.
Amylin-Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease.
复制标题
使用分子动力学模拟在原子分辨率下的Amylin-Aβ低聚物：2型糖尿病与阿尔茨海默氏病之间的联系。
DOI：
10.1039/c5cp03338a
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发表时间：
2016-01-28
期刊：
影响因子：
--
通讯作者：
Miller Y
中科院分区：
文献类型：
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作者：
Baram M;Atsmon-Raz Y;Ma B;Nussinov R;Miller Y
临床研究确定 2 型糖尿病 (T2D) 是阿尔茨海默病 (AD) 的危险因素。连接 T2D 和 AD 的潜在机制之一是与退行性变化相关的细胞损失。 Amylin1-37 聚集体（T2D 中的病理种类）与 Aβ1-42（AD 中的病理种类）共定位，形成 Amylin1-37-Aβ1-42 斑块，促进聚集，从而促进 AD 的病因学。然而，Amylin1-37 与 Aβ1-42 共聚集的机制仍不清楚。这项工作展示了 Amylin1-37 寡聚物和 Aβ1-42 寡聚物之间在原子分辨率下的相互作用，对相对较大的交叉接种 Amylin1-37 -Aβ1-42 寡聚物集合应用了广泛的分子动力学模拟。本研究的主要结论是：第一，Aβ1-42寡聚体更喜欢与Amylin1-37寡聚体相互作用形成单层构象（注册内相互作用）而不是双层构象；其次，在交叉接种的Amylin1-37-Aβ1-42寡聚物的一些双层构象中，Amylin1-37寡聚物使Aβ1-42寡聚物不稳定，从而抑制Aβ1-42聚集，而在其他双层构象中，Amylin1-37寡聚物稳定Aβ1-42寡聚物，从而促进Aβ1-42聚集。
Clinical studies identified Type 2 diabetes (T2D) as a risk factor of Alzheimer's disease (AD). One of the potential mechanisms that link T2D and AD is the loss of cells associated with degenerative changes. Amylin1-37 aggregates (the pathological species in T2D) were found to be co-localized with those of Aβ1-42 (the pathological species in AD) to form the Amylin1-37-Aβ1-42 plaques, promoting aggregation and thus contributing to the etiology of AD. However, the mechanisms by which Amylin1-37 co-aggregate with Aβ1-42 are still elusive. This work presents the interactions between Amylin1-37 oligomers and Aβ1-42 oligomers at atomic resolution applying extensive molecular dynamics simulations for relatively large ensemble of cross-seeding Amylin1-37 -Aβ1-42 oligomers. The main conclusions of this study are first, Aβ1-42 oligomers prefer to interact with Amylin1-37 oligomers to form single layer conformations (in-register interactions) rather than double layer conformations; and second, in some double layer conformations of the cross-seeding Amylin1-37 -Aβ1-42 oligomers, the Amylin1-37 oligomers destabilize the Aβ1-42 oligomers and thus inhibit Aβ1-42 aggregation, while in other double layer conformations, the Amylin1-37 oligomers stabilize Aβ1-42 oligomers and thus promote Aβ1-42 aggregation.