Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, 92265, Fontenay-aux-Roses, France.
MIRCen, INSERM-CEA, Platform for experimental pathology, U1169 and US27, F-92265 Fontenay-aux-Roses, France.
Brain. 2021 May 7;144(4):1167-1182. doi: 10.1093/brain/awab011.
Deposits of different abnormal forms of tau in neurons and astrocytes represent key anatomo-pathological features of tauopathies. Although tau protein is highly enriched in neurons and poorly expressed by astrocytes, the origin of astrocytic tau is still elusive. Here, we used innovative gene transfer tools to model tauopathies in adult mouse brains and to investigate the origin of astrocytic tau. We showed in our adeno-associated virus (AAV)-based models and in Thy-Tau22 transgenic mice that astrocytic tau pathology can emerge secondarily to neuronal pathology. By designing an in vivo reporter system, we further demonstrated bidirectional exchanges of tau species between neurons and astrocytes. We then determined the consequences of tau accumulation in astrocytes on their survival in models displaying various status of tau aggregation. Using stereological counting of astrocytes, we report that, as for neurons, soluble tau species are highly toxic to some subpopulations of astrocytes in the hippocampus, whereas the accumulation of tau aggregates does not affect their survival. Thus, astrocytes are not mere bystanders of neuronal pathology. Our results strongly suggest that tau pathology in astrocytes may significantly contribute to clinical symptoms.
神经元和星形胶质细胞中不同异常形式的 tau 沉积物是 tau 病的主要解剖病理学特征。尽管 tau 蛋白在神经元中高度富集，而在星形胶质细胞中表达水平较低，但星形胶质细胞 tau 的来源仍不清楚。在这里，我们使用创新的基因转移工具在成年小鼠大脑中模拟 tau 病，并研究星形胶质细胞 tau 的起源。我们在基于腺相关病毒 (AAV) 的模型和 Thy-Tau22 转基因小鼠中表明，星形胶质细胞 tau 病理学可以继发于神经元病理学。通过设计体内报告系统，我们进一步证明了 tau 物种在神经元和星形胶质细胞之间的双向交换。然后，我们确定了在显示 tau 聚集不同状态的模型中，tau 在星形胶质细胞中的积累对其存活的影响。通过对星形胶质细胞的体视学计数，我们报告说，与神经元一样，可溶性 tau 物种对海马体中某些亚群的星形胶质细胞具有高度毒性，而 tau 聚集物的积累不会影响它们的存活。因此，星形胶质细胞并非神经元病理学的旁观者。我们的结果强烈表明，星形胶质细胞中的 tau 病理学可能对临床症状有重大贡献。
