Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo.
Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo.
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抗TAU抗体可在体外阻断tau骨料播种显着降低病理并改善体内认知。
DOI：
10.1016/j.neuron.2013.07.046
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发表时间：
2013-10-16
期刊：
影响因子：
16.2
通讯作者：
Holtzman DM
中科院分区：
文献类型：
--
作者：
Yanamandra K;Kfoury N;Jiang H;Mahan TE;Ma S;Maloney SE;Wozniak DF;Diamond MI;Holtzman DM
Tau聚集发生在神经退行性疾病中，包括阿尔茨海默病和统称为Tau病的许多其他病症。由细胞外tau聚集体介导的tau病变的跨细胞传播可能是这些病症的发病机制的基础。P301S tau转基因小鼠表达突变的人tau蛋白，并发展进行性tau病理学。使用基于细胞的生物传感器测定，我们筛选了抗tau单克隆抗体阻断P301S脑裂解物中存在的接种活性的能力。我们将3种有效的抗体或对照注入P301S小鼠的侧脑室，持续3个月。抗体显著减少过度磷酸化、聚集和不溶性tau蛋白。它们还阻断了使用生物传感器测定在脑裂解物中检测到的tau接种活性的发展，减少了小胶质细胞活化，并改善了认知缺陷。这些数据暗示了细胞外tau聚集体在病理学发展中的核心作用。他们还建议专门设计用于阻断跨细胞聚集体传播的免疫疗法将是一种有效的治疗策略。
Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein, and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused 3 effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.
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