Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

中文翻译：

---

Fyn 激酶抑制减少蛋白质聚集，增加突触密度并改善转基因和创伤性 Tau 蛋白病的记忆。

错误折叠的磷酸化 Tau（Tau 蛋白病）的积累可由突变或创伤引发，并与突触丢失、神经胶质增生、神经变性和记忆缺陷有关。Fyn 激酶与 Tau 物理结合并调节亚细胞分布。在这里，我们评估了药理学 Fyn 抑制是否会改变 Tauopathy。在 P301S 转基因小鼠中，慢性 Fyn 抑制可防止空间记忆和被动回避学习的缺陷。行为的改善与海马中磷酸-Tau 的积累减少、神经胶质激活的减少和突触前标志物的恢复相结合。我们将此分析扩展到创伤模型，其中非常轻微的重复性闭合性头部损伤与 2 周内的慢性可变压力相结合，以产生持续的记忆缺陷和 Tau 积累。在这个模型中，创伤结束后 24 小时开始的 Fyn 抑制挽救了记忆表现并减少了磷酸-Tau 的积累。因此，抑制 Fyn 激酶可能对临床 Tauo 病具有治疗益处。