Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid β (Aβ) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aβ-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22). Subsequent phenotype analysis of P2X7-deficient Tau mice revealed the instrumental impact of this purinergic receptor. Indeed, while P2X7-deficiency had a moderate effect on Tau pathology itself, we observed a significant reduction of microglia activation and of Tau-related inflammatory mediators, particularly CCL4. Importantly, P2X7 deletion ultimately rescued synaptic plasticity and memory impairments of Tau mice. Altogether, the present data support a contributory role of P2X7 dysregulation on processes governing Tau-induced brain anomalies. Due to the convergent role of P2X7 blockade in both Aβ and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies.

阿尔茨海默病是最常见的痴呆形式，其特征在于细胞内过度磷酸化的 Tau 蛋白聚集和淀粉样蛋白 β (Aβ) 肽的细胞外聚集。我们之前证明了嘌呤能受体 P2X7 (P2X7) 在 Aβ 介导的神经变性中起主要作用，但 P2X7 和 Tau 之间的关系仍然被忽视。这种联系得到了各种类型额颞叶变性患者皮层 P2X7 上调的支持，包括 Tau 编码基因 MAPT 以及 Tauopathy 小鼠模型 (THY-Tau22) 的大脑中的突变。随后对 P2X7 缺陷型 Tau 小鼠的表型分析揭示了这种嘌呤能受体的重要影响。事实上，虽然 P2X7 缺乏对 Tau 病理学本身有中等影响，我们观察到小胶质细胞活化和 Tau 相关炎症介质，特别是 CCL4 显着减少。重要的是，P2X7 缺失最终挽救了 Tau 小鼠的突触可塑性和记忆障碍。总之，目前的数据支持 P2X7 失调对控制 Tau 诱导的脑异常的过程的贡献作用。由于 P2X7 阻断在 Aβ 和 Tau 背景中的聚合作用，P2X7 抑制剂可能被证明是抑制阿尔茨海默病和 Tau 病的毁灭性认知衰退的理想候选药物。目前的数据支持 P2X7 失调对控制 Tau 诱导的脑异常的过程的贡献作用。由于 P2X7 阻断在 Aβ 和 Tau 背景中的收敛作用，P2X7 抑制剂可能被证明是抑制阿尔茨海默病和 Tau 病的毁灭性认知衰退的理想候选药物。目前的数据支持 P2X7 失调对控制 Tau 诱导的脑异常的过程的贡献作用。由于 P2X7 阻断在 Aβ 和 Tau 背景中的聚合作用，P2X7 抑制剂可能被证明是抑制阿尔茨海默病和 Tau 病的毁灭性认知衰退的理想候选药物。