Ali Abid, Matveyenka Mikhail, Pickett Davis N, Rodriguez Axell, Kurouski Dmitry
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
J Neurochem. 2025 Jan;169(1):e16294. doi: 10.1111/jnc.16294.
A hallmark of Alzheimer disease (AD) and tauopathies, severe neurodegenerative diseases, is the progressive aggregation of Tau, also known as microtubule-associated Tau protein. Full-length Tau, also known as 2N4R, contains two N-terminal inserts that bind to tubulin. This facilitates the self-assembly of tubulin simultaneously enhancing stability of cell microtubules. Other Tau isoforms have one (1N4R) or zero (0N4R) N-terminal inserts, which makes 2N4R Tau more and 0N4R less effective in promoting microtubule self-assembly. A growing body of evidence indicates that lipids can alter the aggregation rate of Tau isoforms. However, the role of N-terminal inserts in Tau-lipid interactions remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which N-terminal inserts alter interactions of Tau isoforms with cholesterol, one of the most important lipids in plasma membranes. Our results showed that 2 N insert prevents amyloid-driven aggregation of Tau at the physiological concentration of cholesterol, while the absence of this N-terminal repeat (1N4R and 0N4R Tau) resulted in the self-assembly of Tau into toxic amyloid fibrils. We also found that the presence of cholesterol in the lipid bilayers caused a significant increase in the cytotoxicity of 1N4R and 0N4R Tau to neurons. This effect was not observed for 2N4R Tau fibrils formed in the presence of lipid membranes with low, physiological, and elevated concentrations of cholesterol. Using molecular assays, we found that Tau aggregates primarily exert cytotoxicity by damaging cell endosomes, endoplasmic reticulum, and mitochondria.
阿尔茨海默病（AD）和tau蛋白病是严重的神经退行性疾病，其一个标志是Tau蛋白（也称为微管相关Tau蛋白）的进行性聚集。全长Tau蛋白，也称为2N4R，包含两个与微管蛋白结合的N端插入序列。这有助于微管蛋白的自组装，同时增强细胞微管的稳定性。其他Tau异构体有一个（1N4R）或零个（0N4R）N端插入序列，这使得2N4R Tau在促进微管自组装方面更有效，而0N4R则效果较差。越来越多的证据表明，脂质可以改变Tau异构体的聚集速率。然而，N端插入序列在Tau-脂质相互作用中的作用仍不清楚。在本研究中，我们利用了一系列生物物理方法来确定N端插入序列在多大程度上改变了Tau异构体与胆固醇（质膜中最重要的脂质之一）的相互作用。我们的结果表明，在生理浓度的胆固醇条件下，2N插入序列可防止Tau蛋白由淀粉样蛋白驱动的聚集，而缺乏该N端重复序列（1N4R和0N4R Tau）则导致Tau蛋白自组装成有毒的淀粉样纤维。我们还发现，脂质双层中胆固醇的存在导致1N4R和0N4R Tau对神经元的细胞毒性显著增加。在低、生理和高浓度胆固醇的脂质膜存在下形成的2N4R Tau纤维未观察到这种效应。通过分子分析，我们发现Tau聚集体主要通过损伤细胞内体、内质网和线粒体来发挥细胞毒性。
