PDF(Pubmed)
Abstract：
Alzheimer\'s disease is the fastest-growing neurodegenerative disease that affects over six million Americans. The abnormal aggregation of amyloid β peptide and Tau protein is the expected molecular cause of the loss of neurons in brains of AD patients. A growing body of evidence indicates that lipids can alter the aggregation rate of amyloid β peptide and modify the toxicity of amyloid β aggregates. However, the role of lipids in Tau aggregation remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which phospatidylserine (PS) altered the aggregation properties of Tau isoforms with one (1N4R) and two (2N4R) N terminal inserts that enhance the binding of Tau to tubulin. We found that the length and saturation of fatty acids (FAs) in PS altered the aggregation rate of 2N4R isoform, while no changes in the aggregation rate of 1N4R were observed. These results indicate that N terminal inserts play an important role in protein-lipid interactions. We also found that PS could change the toxicity of 1N4R and 2N4R Tau fibrils, as well as alter molecular mechanisms by which these aggregates exert cytotoxicity to neurons. Finally, we found that although Tau fibrils formed in the presence and absence of PS endocytosed by cells, only fibril species that were formed in the presence of PS exert strong impairment of the cell mitochondria.
摘要：
阿尔茨海默病是增长最快的神经退行性疾病，影响超过600万美国人。淀粉样β肽和Tau蛋白的异常聚集是AD患者脑中神经元丢失的预期分子原因。越来越多的证据表明，脂质可以改变淀粉样β肽的聚集速率并改变淀粉样β聚集体的毒性。然而,脂质在Tau聚集中的作用尚不清楚.在这项研究中,我们利用一组生物物理方法来确定磷酸基丝氨酸(PS)改变Tau同工型聚集特性的程度,其中1个(1N4R)和2个(2N4R)N末端插入增强Tau与微管蛋白的结合.我们发现PS中脂肪酸（FAs）的长度和饱和度改变了2N4R同工型的聚集速率，而1N4R的聚集率没有观察到变化。这些结果表明N末端插入物在蛋白质-脂质相互作用中起重要作用。我们还发现PS可以改变1N4R和2N4RTau原纤维的毒性，以及改变这些聚集体对神经元产生细胞毒性的分子机制。最后,我们发现，尽管Tau原纤维在存在和不存在PS的情况下被细胞内吞形成，只有在PS存在下形成的原纤维物种对细胞线粒体产生强烈损害。
