Clustering of Tau Fibrils Impairs the Synaptic Composition of ?3-Na+/K+-ATPase and AMPA receptors

Tau assemblies have prion-like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion-like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau form clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+-ATPase (NKA), and AMPA receptors. The consequence of the clustering is a reduction in the amount of ?3-NKA and an increase in the amount of GluA2-AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA-complexes. Tau and ?-synuclein aggregates often co-exist in patients' brains. We now bring evidences for cross-talk between these pathogenic aggregates with -synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar -synuclein and Tau cross-talk at the plasma membrane imbalances neuronal homeostasis.

Tau聚集体（Tau assemblies）具有朊病毒样特性：它们可在神经元间传播，并通过种子化内源性Tau的聚集实现扩增。尽管外源性Tau聚集体与未致敏神经元细胞膜的结合是朊病毒样传播的关键环节，但其具体机制尚未明确。本研究发现，原纤维状Tau（fibrillar Tau）可通过侧向扩散在细胞膜表面形成聚集簇。我们观察到，此类原纤维可与钠钾ATP酶（Na+/K+-ATPase）以及AMPA受体（AMPA receptors）相结合。该聚集过程会导致突触处的?3-NKA蛋白水平降低，同时使GluA2亚型AMPA受体的突触定位增加。此外，原纤维状Tau还会破坏功能性钠钾ATP酶复合物的稳定性。Tau与α-突触核蛋白（α-synuclein）聚集体在患者大脑中常共同存在，本研究为这两种致病性聚集体间的交叉串扰提供了证据：α-突触核蛋白原纤维可显著增强原纤维状Tau的聚集能力及其突触定位。我们的研究结果提示，原纤维状α-突触核蛋白与Tau在细胞膜上的相互串扰会打破神经元的稳态平衡。