Laboratory of Theoretical and Computational Biophysics & Faculty of Applied Sciences, Ton Duc Thang University, 33000 Ho Chi Minh City, Vietnam.
Laboratoire de Biochimie Théorique, CNRS, Université de Paris, UPR 9080, 13 rue Pierre et Marie Curie, 75005 Paris, France.
J Phys Chem B. 2021 Apr 1;125(12):3105-3113. doi: 10.1021/acs.jpcb.1c00030. Epub 2021 Mar 19.
Three amino acid substitutions distinguish rat and human Aβ42 peptides and contribute to the difference in toxicity properties. Indeed, aged rodents rarely develop the characteristic lesions of Alzheimer's disease in contrast to humans. Both peptides form, however, amyloid fibrils in buffer solution, but their affinities to the membrane vary. In particular, there is experimental evidence that the rat Aβ42 peptide does not induce Ca fluxes in cells. We recently designed a tetrameric β-barrel structure and showed that this model is severely destabilized for Aβ40 human compared to its Aβ42 human counterpart, explaining the absence of ionic currents of Aβ40 in planar lipid bilayers. In this study, we asked whether our model is destabilized for the rat Aβ42 peptide by using extensive replica exchange molecular dynamics simulation in a dipalmitoylphosphatidylcholine (DPPC) lipid bilayer membrane. Our results show that the much lower propensity of aged rodents to develop Alzheimer's disease symptoms might be correlated to its tetrameric β-barrel stability in the cell membrane.
三个氨基酸取代区分了大鼠和人类的 Aβ42 肽，并导致了毒性特性的差异。事实上，与人类相比，年老的啮齿动物很少出现阿尔茨海默病的典型病变。两种肽都能在缓冲溶液中形成淀粉样纤维，但它们与膜的亲和力不同。特别是，有实验证据表明，大鼠 Aβ42 肽不会诱导细胞内的 Ca 流。我们最近设计了一个四聚体 β-桶结构，并表明与人类 Aβ42 相比，该模型对人类 Aβ40 的稳定性严重降低，这解释了在平面脂质双层中 Aβ40 没有离子电流。在这项研究中，我们通过在二棕榈酰磷脂酰胆碱 (DPPC) 脂质双层膜中使用广泛的复制交换分子动力学模拟来询问我们的模型是否因大鼠 Aβ42 肽而不稳定。我们的结果表明，年老的啮齿动物患阿尔茨海默病症状的倾向较低，可能与其在细胞膜中的四聚体 β-桶稳定性有关。
