The simultaneous accumulation of multiple pathological proteins, such as hyperphosphorylated tau (hp-tau) and phosphorylated α-synuclein (p-αSyn), has been reported in the brains of patients with various neurodegenerative diseases. We previously demonstrated that hp-tau-dependent p-αSyn accumulation was associated with the activation of GSK-3β in the brains of P301L tau transgenic mice. To confirm the effects of another mutant tau on p-αSyn accumulation in vivo, we herein examined the brains of PS19 mice that overexpress human P301S mutant tau. Immunohistochemically, hp-tau and p-αSyn aggregates were detected in the same neuronal cells in the cerebrum and brain stem of aged PS19 mice. A semiquantitative analysis showed a positive correlation between hp-tau and p-αSyn accumulation. Furthermore, an activated form of GSK-3β was detected within cells containing both hp-tau and p-αSyn aggregates in PS19 mice. Western blotting showed a decrease in inactivated PP2A levels in PS19 mice. The present results suggest that the overexpression of human P301S mutant tau induces p-αSyn accumulation that is accompanied by not only GSK-3β, but also PP2A activation in PS19 mice, and highlight the synergic effects between tau and αSyn in the pathophysiology of neurodegenerative diseases that show the codeposition of tau and αSyn.

中文翻译：

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Tauopathy PS19 小鼠模型中磷酸化 α-突触核蛋白的沉积和 GSK-3β 和 PP2A 的激活

据报道，在患有各种神经退行性疾病的患者的大脑中，多种病理蛋白同时积累，例如过度磷酸化的 tau (hp-tau) 和磷酸化的 α-突触核蛋白 (p-αSyn)。我们之前证明了 hp-tau 依赖性 p-αSyn 积累与 P301L tau 转基因小鼠大脑中 GSK-3β 的激活有关。为了证实另一种突变体 tau 对体内 p-αSyn 积累的影响，我们在此检查了过度表达人类 P301S 突变体 tau 的 PS19 小鼠的大脑。在免疫组织化学上，在老年 PS19 小鼠大脑和脑干的相同神经元细胞中检测到 hp-tau 和 p-αSyn 聚集体。半定量分析显示 hp-tau 和 p-αSyn 积累之间呈正相关。此外，在 PS19 小鼠中，在含有 hp-tau 和 p-αSyn 聚集体的细胞中检测到活化形式的 GSK-3β。Western印迹显示PS19小鼠中灭活的PP2A水平降低。目前的结果表明，人 P301S 突变体 tau 的过表达诱导 p-αSyn 积累，这不仅伴随着 GSK-3β，而且在 PS19 小鼠中也伴随着 PP2A 激活，并突出了 tau 和 αSyn 在神经退行性疾病的病理生理学中的协同作用显示 tau 和 αSyn 的共位。