Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression
Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression
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DOI：
10.1111/j.1460-9568.2008.06084.x
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发表时间：
2008-03-01
影响因子：
3.4
通讯作者：
Ko, Li-Wen
中科院分区：
文献类型：
--
作者：
Hamano, Tadanori;Gendron, Tania F.;Ko, Li-Wen
tau聚集体的细胞内组装是阿尔茨海默病和统称为tau蛋白病的其他神经退行性疾病共有的病理学标志。为了模拟tau蛋白病中tau蛋白原纤维形成如何演变，我们先前从诱导表达人tau蛋白的人神经母细胞瘤BE（2）-M17 D细胞建立了转染子M1 C培养物。在本研究中，这些细胞用于确定自噬-溶酶体系统在野生型tau蛋白降解和聚集中的作用。Tau诱导5天导致Tau的积累，其中Tau聚集体在细胞内的标称组装。当在tau诱导终止后加入溶酶体促剂氯喹（CQ）时，tau清除延迟。观察到tau截短减少和完整tau水平增加。当在tau诱导期间存在时，CQ导致tau积累并促进含有截短的和全长tau的肌氨酸不溶性聚集体的形成。CQ处理显著降低了组织蛋白酶D、B和L的活性，并且组织蛋白酶B和L的抑制模拟了CQ的作用并增加了细胞中的tau水平。此外，细胞暴露于自噬抑制剂3-甲基腺嘌呤导致tau蛋白积累和聚集。这些结果表明，自噬-溶酶体系统在tau的清除中起作用，并且该系统的功能障碍导致tau寡聚体和不溶性聚集体的形成。
The intracellular assembly of tau aggregates is a pathological hallmark shared by Alzheimer's disease and other neurodegenerative disorders known collectively as tauopathies. To model how tau fibrillogenesis evolves in tauopathies, we previously established transfectant M1C cultures from human neuroblastoma BE(2)-M17D cells that inducibly express human tau. In the present study, these cells were used to determine the role of the autophagic-lysosomal system in the degradation and aggregation of wild-type tau. Tau induction for 5 days led to the accumulation of tau with nominal assembly of tau aggregates within cells. When the lysosomotropic agent, chloroquine (CQ), was added following the termination of tau induction, tau clearance was delayed. Decreased tau truncation and increased levels of intact tau were observed. When present during tau induction, CQ led to tau accumulation and promoted the formation of sarkosyl-insoluble aggregates containing both truncated and full-length tau. CQ treatment significantly decreased the activities of cathepsins D, B and L, and the inhibition of cathepsins B and L mimicked the effect of CQ and increased tau levels in cells. Additionally, exposure of cells to the autophagy inhibitor, 3-methyladenine, led to tau accumulation and aggregation. These results suggest that the autophagic-lysosomal system plays a role in the clearance of tau, and that dysfunction of this system results in the formation of tau oligomers and insoluble aggregates.