Department of Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute of Brain Research, Faculty of Medicine, Jahnallee 59, University of Leipzig, 04109 Leipzig, Germany.
J Biol Chem. 2012 Dec 21;287(52):43223-33. doi: 10.1074/jbc.M112.396176. Epub 2012 Nov 5.
The microtubule-associated protein Tau is mainly expressed in neurons, where it binds and stabilizes microtubules. In Alzheimer disease and other tauopathies, Tau protein has a reduced affinity toward microtubules. As a consequence, Tau protein detaches from microtubules and eventually aggregates into β-sheet-containing filaments. The fibrillization of monomeric Tau to filaments is a multistep process that involves the formation of various aggregates, including spherical and protofibrillar oligomers. Previous concepts, primarily developed for Aβ and α-synuclein, propose these oligomeric intermediates as the primary cytotoxic species mediating their deleterious effects through membrane permeabilization. In the present study, we thus analyzed whether this concept can also be applied to Tau protein. To this end, viability and membrane integrity were assessed on SH-SY5Y neuroblastoma cells and artificial phospholipid vesicles, treated with Tau monomers, Tau aggregation intermediates, or Tau fibrils. Our findings suggest that oligomeric Tau aggregation intermediates are the most toxic compounds of Tau fibrillogenesis, which effectively decrease cell viability and increase phospholipid vesicle leakage. Our data integrate Tau protein into the class of amyloidogenic proteins and enforce the hypothesis of a common toxicity-mediating mechanism for amyloidogenic proteins.
微管相关蛋白 Tau 主要在神经元中表达，在那里它结合并稳定微管。在阿尔茨海默病和其他 Tau 病中，Tau 蛋白对微管的亲和力降低。结果，Tau 蛋白从微管上脱离，最终聚集形成含有 β-片层的纤维。单体 Tau 向纤维的纤维化是一个多步骤的过程，涉及到各种聚集体的形成，包括球形和原纤维寡聚物。以前的概念，主要是为 Aβ 和 α-突触核蛋白开发的，提出这些寡聚体中间物作为介导其通过膜通透性产生有害影响的主要细胞毒性物质。在本研究中，我们因此分析了这个概念是否也可以应用于 Tau 蛋白。为此，我们用 Tau 单体、 Tau 聚集中间物或 Tau 纤维处理 SH-SY5Y 神经母细胞瘤细胞和人工磷脂囊泡，评估了细胞活力和膜完整性。我们的发现表明，寡聚 Tau 聚集中间物是 Tau 纤维形成过程中最具毒性的化合物，它们有效地降低了细胞活力并增加了磷脂囊泡的渗漏。我们的数据将 Tau 蛋白纳入淀粉样蛋白原蛋白类，并加强了淀粉样蛋白原蛋白具有共同毒性介导机制的假设。
