Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico 87131.
Biomedical Engineering Graduate Program, University of New Mexico, Albuquerque, New Mexico 87131.
J Biol Chem. 2019 Oct 18;294(42):15304-15317. doi: 10.1074/jbc.RA119.010003. Epub 2019 Aug 22.
The aggregation of the tau protein into neurofibrillary tangles is believed to correlate with cognitive decline in several neurodegenerative disorders, including Alzheimer's disease. Recent studies suggest that tau's interactions with the cell membrane could serve as a toxicity pathway and also enhance fibrillation into paired helical filaments (PHFs). Conformational changes associated with tau-membrane interactions are poorly understood, and their characterization could improve our understanding of tau pathogenicity. In this study, we investigated the molecular level structural changes associated with the interaction of the tau hexapeptide PHF6 with model lipid membranes and characterized the effects of these interactions on membrane stability and peptide fibrillation. We used two PHF6 forms, the aggregation-prone PHF6 with N-terminal acetylation (Ac-PHF6) and the non-aggregation prone PHF6 with a standard N terminus (NH-PHF6). We found that both PHF6 peptides are neurotoxic and exhibit similar membrane-mediated changes, consisting of: 1) favorable interactions with anionic membranes, 2) membrane destabilization through lipid extraction, and 3) membrane-mediated fibrillation. The rate at which these changes occurred was the main difference between the two peptides. NH-PHF6 displayed slow membrane-mediated fibrillation after 6 days of incubation, whereas Ac-PHF6 adopted a β-sheet conformation at the surface of the membrane within hours. Ac-PHF6 interactions with the membrane were also accompanied by membrane invagination and rapid membrane destabilization. Overall, our results reveal that membrane interactions could play a critical role in tau toxicity and fibrillation, and highlight that unraveling these interactions is important for significantly advancing the development of therapeutic strategies to manage tau-associated neurodegenerative diseases.
tau 蛋白的聚集形成神经纤维缠结被认为与几种神经退行性疾病（包括阿尔茨海默病）的认知能力下降有关。最近的研究表明，tau 与细胞膜的相互作用可能作为一种毒性途径，并增强其纤维化形成双螺旋丝（PHF）。与 tau 与细胞膜相互作用相关的构象变化尚未得到充分理解，对其特征的描述可以加深我们对 tau 致病性的理解。在这项研究中，我们研究了与 tau 六肽 PHF6 与模型脂质膜相互作用相关的分子水平结构变化，并描述了这些相互作用对膜稳定性和肽纤维化的影响。我们使用了两种 PHF6 形式，具有 N 端乙酰化（Ac-PHF6）的易于聚集的 PHF6 和具有标准 N 端的不易聚集的 PHF6（NH-PHF6）。我们发现，这两种 PHF6 肽都具有神经毒性，并表现出类似的膜介导变化，包括：1）与阴离子膜的有利相互作用，2）通过脂质提取导致的膜不稳定，3）膜介导的纤维化。这些变化发生的速度是这两种肽之间的主要区别。NH-PHF6 在孵育 6 天后显示出缓慢的膜介导纤维化，而 Ac-PHF6 在数小时内就在膜表面采用β-折叠构象。Ac-PHF6 与膜的相互作用还伴随着膜内陷和快速的膜不稳定。总的来说，我们的结果表明，膜相互作用可能在 tau 毒性和纤维化中起关键作用，并强调阐明这些相互作用对于显著推进治疗策略的开发以管理与 tau 相关的神经退行性疾病非常重要。
