Tyagi Mitali, Chadha Radhika, de Hoog Eric, Sullivan Kaelan R, Walker Alicia C, Northrop Ava, Fabian Balazs, Fuxreiter Monika, Hyman Bradley T, Shepherd Jason D
Department of Neurobiology, University of Utah, Salt Lake City, USA.
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Germany.
bioRxiv. 2024 Oct 22:2024.10.22.619703. doi: 10.1101/2024.10.22.619703.
Intracellular neurofibrillary tangles that consist of misfolded tau protein cause neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau pathology spreads cell-to-cell but the exact mechanisms of tau release and intercellular transmission remain poorly defined. Tau is released from neurons as free protein or in extracellular vesicles (EVs) but the role of these different release mechanisms in intercellular tau transmission is unclear. Here, we show that the neuronal gene Arc is critical for packaging tau into EVs. Brain EVs purified from human tau (hTau) transgenic rTg4510 mice (rTg) contain high levels of hTau that are capable of seeding tau pathology. In contrast, EVs purified from rTg crossed with Arc knock-out mice (rTg) have significantly less hTau and cannot seed tau aggregation. Arc facilitates the release of hTau in EVs produced via the I-BAR protein IRSp53, but not free tau. Arc protein directly binds hTau to form a fuzzy complex that we identified in both mouse and human brain tissue. We find that pathological intracellular hTau accumulates in neurons in rTg mice, which correlates with accelerated neuron loss in the hippocampus. Finally, we find that intercellular tau transmission is significantly abrogated in Arc KO mice. We conclude that Arc-dependent release of tau in EVs plays a significant role in intracellular tau elimination and intercellular tau transmission.
由错误折叠的tau蛋白组成的细胞内神经原纤维缠结会导致阿尔茨海默病（AD）和额颞叶痴呆（FTD）中的神经退行性变。tau病理在细胞间传播，但tau释放和细胞间传播的确切机制仍不清楚。tau以游离蛋白或细胞外囊泡（EVs）的形式从神经元中释放出来，但这些不同释放机制在细胞间tau传播中的作用尚不清楚。在这里，我们表明神经元基因Arc对于将tau包装到EVs中至关重要。从人类tau（hTau）转基因rTg4510小鼠（rTg）中纯化的脑EVs含有高水平的hTau，能够引发tau病理。相比之下，从与Arc基因敲除小鼠杂交的rTg中纯化的EVs含有明显较少的hTau，并且不能引发tau聚集。Arc促进通过I-BAR蛋白IRSp53产生的EVs中hTau的释放，但不促进游离tau的释放。Arc蛋白直接与hTau结合形成一种模糊复合物，我们在小鼠和人类脑组织中都鉴定到了这种复合物。我们发现病理性细胞内hTau在rTg小鼠的神经元中积累，这与海马体中神经元损失加速相关。最后，我们发现Arc基因敲除小鼠中的细胞间tau传播显著减少。我们得出结论，Arc依赖的EVs中tau的释放在细胞内tau清除和细胞间tau传播中起重要作用。
