AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.
AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.
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DOI：
10.1084/jem.20162125
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Holtzman DM
中科院分区：
文献类型：
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作者：
Ising C;Gallardo G;Leyns CEG;Wong CH;Jiang H;Stewart F;Koscal LJ;Roh J;Robinson GO;Remolina Serrano J;Holtzman DM
Ising等人报道了通过AAV介导的基因转移在tau蛋白病小鼠模型的脑中表达抗tau scFv。治疗的小鼠显示出显著降低的tau过度磷酸化和去污剂可溶性tau种类。因此，Fc结构域不需要介导tau蛋白病的作用。tau蛋白病的特征在于过度磷酸化的聚集形式的tau蛋白的进行性积累。我们的实验室以前已经证明，被动免疫与抗tau抗体，HJ 8.5，减少积累的病理性tau在人P301S tau表达转基因（P301S-tg）小鼠模型的额颞叶痴呆/tau病变。为了研究HJ8.5的Fc结构域是否是治疗效果所需的，我们工程化了来源于HJ8.5的具有可变接头长度的单链可变片段（scFv），其全部对人tau特异性。基于不同的结合特性，我们选择了两种抗tau scFv，并通过腺相关病毒介导的基因转移到P301S-tg小鼠的脑中来测试它们的体内功效。scFv显著降低了P301S-tg小鼠脑组织中过度磷酸化的聚集tau的水平，这与洗涤剂可溶性tau种类的减少有关。有趣的是，这些小鼠在脑脊液中显示出相当水平的scFv，而对总细胞外tau水平没有显著影响。因此，我们的研究为抗tau免疫治疗提供了一种新的策略，可能限制有害的促炎反应。
Ising et al. report expression of anti-tau scFvs in the brain of a mouse model of tauopathy by AAV-mediated gene transfer. Treated mice show markedly decreased tau hyperphosphorylation and detergent-soluble tau species. Therefore, the Fc domain is not required to mediate effects in tauopathy. Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus–mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.