Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

阿尔茨海默病是至少 26 种以神经元、神经胶质细胞或两者中 tau 阳性积累为特征的疾病之一。然而，目前尚不清楚哪些修饰导致可溶性 tau 转化为不溶性聚集体。我们之前进行了遗传筛选，确定酪氨酸激酶 2 （TYK2） 是 tau 水平的候选调节因子。在这里，我们验证了这一发现，发现 TYK2 在酪氨酸 29 （Tyr29） 位点磷酸化 tau，导致其稳定并促进其在人体细胞中的聚集。我们发现 TYK2 介导的 Tyr29 磷酸化会干扰 tau 的自噬清除。我们还表明，TYK2 介导的 Tyr29 磷酸化促进了 P301S tau 转基因小鼠的病理性 tau 积累。此外，在 tau 病小鼠模型中，敲除 Tyk2 降低了总 tau 和致病性 tau 水平并挽救了神经胶质增生。总的来说，这些数据表明，因此部分抑制 TYK2 可能是降低 tau 水平和毒性的一种策略。