Neuronal tau species transfer to astrocytes and induce their loss according to tau aggregation state
Neuronal tau species transfer to astrocytes and induce their loss according to tau aggregation state
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DOI：
10.1093/brain/awab011
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发表时间：
2021-04-11
期刊：
影响因子：
14.5
通讯作者：
Cambon, Karine
中科院分区：
文献类型：
--
作者：
de Gerando, Anastasie Mate;d'Orange, Marie;Cambon, Karine
神经元和星形胶质细胞中不同异常形式的tau沉积代表了tau病的关键解剖病理特征。虽然tau蛋白在神经元中高度富集，而在星形胶质细胞中表达较差，但星形胶质细胞tau蛋白的起源仍是一个谜。在这里，我们使用创新的基因转移工具来模拟成年小鼠大脑中的tau病变，并研究星形细胞tau的起源。我们在基于腺相关病毒（AAV）的模型和Thy-Tau22转基因小鼠中发现星形细胞tau病理可继发于神经元病理。通过设计一个体内报告系统，我们进一步证明了神经元和星形胶质细胞之间tau物种的双向交换。然后，我们在显示各种tau聚集状态的模型中确定星形胶质细胞中tau积聚对其存活的影响。利用星形胶质细胞的体视学计数，我们报道，对于神经元，可溶性tau物质对海马中星形胶质细胞的某些亚群具有高毒性，而tau聚集体的积累并不影响它们的存活。因此，星形胶质细胞不仅仅是神经病理的旁观者。我们的研究结果强烈提示星形胶质细胞中的tau病理可能对临床症状有显著影响。
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.