Tauopathies are neurodegenerative diseases characterized by the presence of aberrant intraneuronal aggregates of hyperphosphorylated Tau protein. Recent studies suggest that associated chronic neuroinflammation may contribute to the pathological Tau dissemination. However, the underlying molecular mechanisms remain unknown. Since purinergic P2 × 7 receptors (P2 × 7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2 × 7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2 × 7 reverted microglial activation in P301S mice leading to a reduction in microglial migratory, secretory, and proliferative capacities, and promoting phagocytic function. Furthermore, it reduced the intraneuronal phosphorylated Tau levels in a GSK3-dependent way and increased extracellular phosphorylated Tau (eTau) levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2 × 7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2 × 7 overexpression caused a significant worsening of Tau-induced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2 × 7 plays a deleterious role in tauopathies and suggest that its blockade may be a promising approach to treat Tauopathies.

Tauopathies 是神经退行性疾病，其特征在于存在异常的神经元内过度磷酸化的 Tau 蛋白聚集体。最近的研究表明，相关的慢性神经炎症可能有助于病理性 Tau 传播。然而，潜在的分子机制仍然未知。由于嘌呤能 P2 × 7 受体 (P2 × 7) 可以感知与神经炎症相关的细胞外 ATP 水平的升高，因此建议其参与神经退行性相关炎症。我们在诊断为不同 tau 病的患者和 tau 病小鼠模型 P301S 小鼠中发现了 P2 × 7 上调。体内P301S 小鼠中 P2 × 7 的药理学或遗传阻断可恢复小胶质细胞的活化，导致小胶质细胞迁移、分泌和增殖能力降低，并促进吞噬功能。此外，它以 GSK3 依赖性方式降低神经元内磷酸化 Tau 水平，并通过降低胞外酶 TNAP 的表达增加细胞外磷酸化 Tau (eTau) 水平。因此，P2 × 7 的药理学或遗传阻断改善了 P301S 小鼠的细胞存活、运动和记忆缺陷以及抗焦虑特性。相反，P2 × 7 过表达导致 Tau 诱导的毒性显着恶化，并加剧了 P301S 小鼠恶化的运动和记忆缺陷。