School of Medicine, Southeast University, Nanjing, China.
Department of Neurology, Affiliated ZhongDa Hospital, Southeast University, Nanjing, China.
Psychiatry Clin Neurosci. 2024 Sep;78(9):517-526. doi: 10.1111/pcn.13704. Epub 2024 Jul 16.
Systemic infections are associated with the development of AD, especially in individuals carrying the APOE4 genotype. However, the detailed mechanism through which APOE4 affects microglia inflammatory response remains unclear.
We obtained human snRNA-seq data from the Synapse AD Knowledge Portal and assessed the DEGs between APOE3 and APOE4 isoforms in microglia. To verify the interaction between ApoE and infectious products, we used ApoE to stimulate in vitro and in vivo models in the presence or absence of LPS (or ATP). The NLRP3 gene knockout experiment was performed to demonstrate whether the APOE-NLRP3 axis was indispensable for microglia to regulate inflammation and mitochondrial autophagy. Results were evaluated by biochemical analyses and fluorescence imaging.
Compared with APOE3, up-regulated genes in APOE4 gene carriers were involved in pro-inflammatory responses. ApoE4-stimulation significantly increased the levels of NLRP3 inflammasomes and ROS in microglia. Moreover, compared with ApoE4 alone, the co-incubation of ApoE4 with LPS (or ATP) markedly promoted pyroptosis. Both NF-κB activation and mitochondrial autophagy dysfunction were contributed by the increased level of NLRP3 inflammasomes induced by ApoE4. Furthermore, the pathological impairment induced by ApoE4 could be reversed by NLRP3 KO.
Our study highlights the importance of NLRP3 inflammasomes in linking ApoE4 with microglia innate immune function. These findings not only provide a molecular basis for APOE4-mediated neuroinflammatory but also reveal the potential reason for the increased risk of AD in APOE4 gene carriers after contracting infectious diseases.
全身感染与 AD 的发生发展相关，尤其在携带 APOE4 基因型的个体中更为明显。然而，APOE4 如何影响小胶质细胞炎症反应的具体机制尚不清楚。
我们从 Synapse AD Knowledge Portal 中获取人类 snRNA-seq 数据，并评估了小胶质细胞中 APOE3 和 APOE4 异构体之间的差异表达基因。为了验证 ApoE 与传染性产物之间的相互作用，我们使用 ApoE 在有或没有 LPS（或 ATP）的情况下刺激体外和体内模型。进行 NLRP3 基因敲除实验，以证明 APOE-NLRP3 轴是否对小胶质细胞调节炎症和线粒体自噬必不可少。通过生化分析和荧光成像评估结果。
与 APOE3 相比，APOE4 基因携带者中上调的基因参与促炎反应。ApoE4 刺激可显著增加小胶质细胞中 NLRP3 炎性小体和 ROS 的水平。此外，与 ApoE4 单独孵育相比，ApoE4 与 LPS（或 ATP）共同孵育可显著促进细胞焦亡。NF-κB 激活和线粒体自噬功能障碍均归因于 ApoE4 诱导的 NLRP3 炎性小体水平增加。此外，NLRP3 KO 可逆转由 ApoE4 引起的病理损伤。
本研究强调了 NLRP3 炎性小体在将 ApoE4 与小胶质细胞固有免疫功能联系起来的重要性。这些发现不仅为 APOE4 介导的神经炎症提供了分子基础，也揭示了 APOE4 基因携带者在感染性疾病后患 AD 的风险增加的潜在原因。
