Abstract：
Abrupt aggregation of amyloid β1-42 (Aβ1-42) peptide in the frontal lobe is the expected underlying cause of Alzheimer\'s disease (AD). β-Sheet-rich oligomers and fibrils formed by Aβ1-42 exert high cell toxicity. A growing body of evidence indicates that lipids can uniquely alter the secondary structure and toxicity of Aβ1-42 aggregates. At the same time, underlying molecular mechanisms that determine this difference in toxicity of amyloid aggregates remain unclear. Using a set of molecular and biophysical assays to determine the molecular mechanism by which Aβ1-42 aggregates formed in the presence of cholesterol, cardiolipin, and phosphatidylcholine exert cell toxicity. Our findings demonstrate that rat neuronal cells exposed to Aβ1-42 fibrils formed in the presence of lipids with different chemical structure exert drastically different magnitude and dynamic of unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria (MT). We found that the opposite dynamics of UPR in MT and ER in the cells exposed to Aβ1-42: cardiolipin fibrils and Aβ1-42 aggregates formed in a lipid-free environment. We also found that Aβ1-42: phosphatidylcholine fibrils upregulated ER UPR simultaneously downregulating the UPR response of MT, whereas Aβ1-42: cholesterol fibrils suppressed the UPR response of ER and upregulated UPR response of MT. We also observed progressively increasing ROS production that damages mitochondrial membranes and other cell organelles, ultimately leading to cell death.
摘要：
淀粉样蛋白β1-42（Aβ1-42）肽在额叶中的突然聚集是阿尔茨海默病（AD）的潜在原因。由Aβ1-42形成的富含β-片层的寡聚体和原纤维发挥高细胞毒性。越来越多的证据表明，脂质可以独特地改变Aβ1-42聚集体的二级结构和毒性。同时,决定淀粉样蛋白聚集体毒性差异的潜在分子机制尚不清楚.使用一组分子和生物物理测定来确定在胆固醇存在下Aβ1-42聚集体形成的分子机制，心磷脂,和磷脂酰胆碱发挥细胞毒性。我们的发现表明，暴露于在具有不同化学结构的脂质存在下形成的Aβ1-42原纤维的大鼠神经元细胞在内质网（ER）和线粒体（MT）中表现出截然不同的未折叠蛋白反应（UPR）的幅度和动态。我们发现暴露于Aβ1-42的细胞中MT和ER中UPR的相反动力学：在无脂环境中形成的心磷脂原纤维和Aβ1-42聚集体。我们还发现Aβ1-42:磷脂酰胆碱原纤维上调ERUPR同时下调MT的UPR反应,而Aβ1-42：胆固醇原纤维抑制ER的UPR反应并上调MT的UPR反应。我们还观察到ROS的产生逐渐增加，破坏线粒体膜和其他细胞器，最终导致细胞死亡。
