Numerous evidences support that microglia contributes to the progression of Alzheimer’s disease. P2X4 receptors are ATP-gated channels with high calcium permeability, which are de novo expressed in a subset of reactive microglia associated with various pathological contexts, contributing to microglial functions. P2X4 receptors are mainly localized in lysosomes and trafficking to the plasma membrane is tightly regulated. Here, we investigated the role of P2X4 in the context of Alzheimer’s disease (AD). Using proteomics, we identified Apolipoprotein E (ApoE) as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B (CatB) activity promoting ApoE degradation; P2rX4 deletion results in higher amounts of intracellular and secreted ApoE in both bone-marrow-derived macrophage (BMDM) and microglia from APP^swe/PSEN1^dE9 brain. In both human AD brain and APP/PS1 mice, P2X4 and ApoE are almost exclusively expressed in plaque-associated microglia. In 12-month-old APP/PS1 mice, genetic deletion of P2rX4 reverses topographical and spatial memory impairment and reduces amount of soluble small aggregates of Aß1-42 peptide, while no obvious alteration of plaque-associated microglia characteristics is observed. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering Aß peptide clearance, which in turn might promotes synaptic dysfunctions and cognitive deficits. Our findings uncover a specific interplay between purinergic signaling, microglial ApoE, soluble Aß (sAß) species and cognitive deficits associated with AD.

大量证据支持小胶质细胞促进阿尔茨海默病的进展。P2X4 受体是具有高钙渗透性的 ATP 门控通道，在与各种病理背景相关的反应性小胶质细胞子集中从头表达，有助于小胶质细胞功能。P2X4 受体主要位于溶酶体中，并且向质膜的运输受到严格调节。在这里，我们研究了 P2X4 在阿尔茨海默病 (AD) 中的作用。利用蛋白质组学，我们将载脂蛋白 E (ApoE) 鉴定为一种特定的 P2X4 相互作用蛋白。我们发现 P2X4 调节溶酶体组织蛋白酶 B (CatB) 活性，促进 ApoE 降解；P2rX4缺失导致骨髓源性巨噬细胞 (BMDM) 和来自 APP ^swe /PSEN1 ^dE9大脑的小胶质细胞中细胞内和分泌的 ApoE 含量更高。在人类 AD 大脑和 APP/PS1 小鼠中，P2X4 和 ApoE 几乎只在斑块相关的小胶质细胞中表达。在 12 个月大的 APP/PS1 小鼠中，P2rX4的基因缺失逆转了地形和空间记忆损伤，并减少了 Aß1-42 肽的可溶性小聚集体的数量，同时没有观察到斑块相关小胶质细胞特征的明显改变。我们的结果支持小胶质细胞 P2X4 促进溶酶体 ApoE 降解，间接改变 Aß 肽清除率，进而可能促进突触功能障碍和认知缺陷。我们的研究结果揭示了嘌呤能信号传导、小胶质细胞 ApoE、可溶性 Aß (sAß) 物种和与 AD 相关的认知缺陷之间的特定相互作用。