Department of Neurology, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany.
Center of Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
ACS Chem Neurosci. 2020 Mar 18;11(6):880-887. doi: 10.1021/acschemneuro.9b00459. Epub 2020 Feb 28.
While fibrillar deposits of hyperphosphorylated protein tau are a key hallmark of several neurodegenerative diseases such as Alzheimer's disease, small oligomers have been speculated to be the key toxic aggregate species. Trivalent metal ions were shown to promote tau oligomer formation . However, little is known about potential intercellular spreading mechanisms or toxic modes of action of such oligomers. We investigated interactions of tau monomers and Fe/Al-induced oligomers with small unilamellar vesicles derived from 1-palmitoyl-2-oleoyl-phosphatidylcholine (neutral, liquid-crystalline phase) and dipalmitoyl-phosphatidylcholine (neutral, gel-phase). We further evaluated the influence of glycogen synthase kinase 3β (GSK-3β)-mediated tau phosphorylation applying the single-particle fluorescence spectroscopy techniques fluorescence correlation spectroscopy, fluorescence intensity distribution analysis, and scanning for intensely fluorescent targets. In these experiments, no binding to neutral lipid surfaces was observed for tau monomers. In contrast, metal-ion-induced tau oligomers showed a gain of function in binding to neutral lipid surfaces. Of note, tau phosphorylation by GSK-3β increased both oligomer formation and membrane affinity of the resulting oligomers. In conclusion, our data imply a pathological gain of function of metal-ion-induced oligomers of hyperphosphorylated tau, enabling membrane binding irrespective of surface charge even at nanomolar protein concentrations.
虽然过度磷酸化蛋白 tau 的纤维状沉积物是几种神经退行性疾病（如阿尔茨海默病）的关键标志，但人们推测小寡聚体是关键的毒性聚集物。三价金属离子被证明能促进 tau 寡聚体的形成。然而，对于这种寡聚体的潜在细胞间传播机制或毒性作用模式知之甚少。我们研究了 tau 单体和 Fe/Al 诱导的寡聚体与源自 1-棕榈酰基-2-油酰基-磷酸胆碱（中性、液晶相）和二棕榈酰基磷酸胆碱（中性、凝胶相）的小单层囊泡的相互作用。我们进一步评估了糖原合酶激酶 3β（GSK-3β）介导的 tau 磷酸化对实验的影响，采用单粒子荧光光谱技术荧光相关光谱、荧光强度分布分析和强荧光靶点扫描。在这些实验中，tau 单体没有与中性脂质表面结合。相比之下，金属离子诱导的 tau 寡聚体在与中性脂质表面结合方面表现出功能获得。值得注意的是，GSK-3β对 tau 的磷酸化既增加了寡聚体的形成，也增加了由此产生的寡聚体与膜的亲和力。总之，我们的数据表明，过度磷酸化的 tau 诱导的金属离子寡聚体具有病理性功能获得，使膜结合成为可能，即使在纳摩尔蛋白浓度下，也不考虑表面电荷。
