Azouz Mehdi, Feuillie Cécile, Lafleur Michel, Molinari Michaël, Lecomte Sophie
Institute of Chemistry and Biology of Membranes and Nano-Objects, CNRS, Université de Bordeaux, INP Bordeaux, UMR5248 allée Geoffroy Saint Hilaire 33600 Pessac France
Department of Chemistry, Université de Montréal Succursale Centre-Ville Montréal C.P. 6128 Québec Canada H3C 3J7.
Nanoscale Adv. 2021 Jun 17;3(14):4244-4253. doi: 10.1039/d1na00055a. eCollection 2021 Jul 13.
One of the hallmarks of Alzheimer's disease (AD) is the formation of neurofibrillary tangles, resulting from the aggregation of the tubulin associated unit protein (Tau), which holds a vital role in maintaining neuron integrity in a healthy brain. The development of such aggregates and their deposition in the brain seem to correlate with the onset of neurodegeneration processes. The misfolding and subsequent aggregation of the protein into paired helical filaments that further form the tangles, lead to dysfunction of the protein with neuronal loss and cognitive decline. The aggregation of the protein then seems to be a causative factor of the neurodegeneration associated with AD. The hypothesis of an involvement of the membrane in modulating the misfolding and assembly of Tau into paired helical filaments attracts increasing interests. To provide more insight about how lipids can modulate the interactions with Tau, we have conducted a comprehensive Atomic Force Microscopy (AFM) study involving supported lipid bilayers of controlled compositions with the Tau microtubule-binding construct K18. Particularly, the effects of zwitterionic and negatively charged phospholipids on the interaction have been investigated. Deleterious solubilization effects have been evidenced on fluid zwitterionic membranes as well as an inability of K18 to fragment gel phases. The role of negative lipids in the aggregation of the peptide and the particular ability of phosphatidylinositol-4,5-bisphosphate (PIP) in inducing K18 fibrillization on membranes are also reported.
阿尔茨海默病（AD）的一个标志性特征是神经原纤维缠结的形成，这是由微管相关单位蛋白（Tau）聚集所致，Tau在维持健康大脑中神经元的完整性方面起着至关重要的作用。此类聚集体的形成及其在大脑中的沉积似乎与神经退行性变过程的开始相关。该蛋白错误折叠并随后聚集成双螺旋丝，进而形成缠结，导致蛋白功能障碍，伴有神经元丧失和认知能力下降。蛋白的聚集似乎是与AD相关的神经退行性变的一个致病因素。膜参与调节Tau错误折叠并组装成双螺旋丝这一假说正吸引着越来越多的关注。为了更深入了解脂质如何调节与Tau的相互作用，我们进行了一项全面的原子力显微镜（AFM）研究，涉及用Tau微管结合构建体K18制备的具有可控组成的支持脂质双层。特别地，研究了两性离子和带负电荷的磷脂对相互作用的影响。已证实在流体两性离子膜上存在有害的溶解作用，以及K18无法使凝胶相碎片化。还报道了负性脂质在肽聚集中的作用以及磷脂酰肌醇 - 4,5 - 二磷酸（PIP）在诱导膜上K18纤维化方面的特殊能力。
