Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea.
Int J Mol Sci. 2020 Feb 7;21(3):1094. doi: 10.3390/ijms21031094.
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a widespread form of dementia. Aggregated forms of the amyloid β-peptide (Aβ) are identified as a toxic species responsible for neuronal damage in AD. Extensive research has been conducted to reveal the aggregation mechanism of Aβ. However, the structure of pathological aggregates and the mechanism of aggregation are not well understood. Recently, experimental studies have confirmed that the α-sheet structure in Aβ drives aggregation and toxicity in AD. However, how the α-sheet structure is formed in Aβ and how it contributes to Aβ aggregation remains elusive. In the present study, molecular dynamics simulations suggest that Aβ adopts the α-strand conformation by peptide-plane flipping. Multiple α-strands interact through hydrogen bonding to form α-sheets. This structure acts as a nucleus that initiates and promotes aggregation and fibrillation of Aβ. Our findings are supported by previous experimental as well as theoretical studies. This study provides valuable structural insights for the design of anti-AD drugs exploiting the α-strand/α-sheet structure.
阿尔茨海默病（AD）是最常见的神经退行性疾病之一，也是一种广泛存在的痴呆症形式。聚集形式的淀粉样 β 肽（Aβ）被认为是导致 AD 神经元损伤的毒性物质。已经进行了广泛的研究来揭示 Aβ 的聚集机制。然而，病理聚集物的结构和聚集机制尚不清楚。最近的实验研究证实，Aβ 中的 α-折叠结构驱动 AD 中的聚集和毒性。然而，Aβ 中的 α-折叠结构是如何形成的，以及它如何促进 Aβ 的聚集，仍然难以捉摸。在本研究中，分子动力学模拟表明，Aβ 通过肽平面翻转采用 α-链构象。多个 α-链通过氢键相互作用形成 α-折叠。这种结构充当核，启动和促进 Aβ 的聚集和纤维化。我们的发现得到了以前的实验和理论研究的支持。这项研究为设计利用 α-链/α-折叠结构的抗 AD 药物提供了有价值的结构见解。
