Synergism of ApoE4 and systemic infectious burden is mediated by the APOE‐NLRP3 axis in Alzheimer's disease

• Published in: Psychiatry and clinical neurosciences Vol. 78; no. 9; pp. 517 - 526
• Main Authors: Liu, Xue‐Ting, Chen, Xiu, Zhao, Na, Geng, Fan, Zhu, Meng‐Meng, Ren, Qing‐Guo
• Format: Journal Article
• Language: English
• Published: Melbourne John Wiley & Sons Australia, Ltd 01.09.2024; Wiley Subscription Services, Inc
• Subjects: activation of microglia; Alzheimer's disease; Apolipoprotein E; Apolipoprotein E4; Autophagy; Genotypes; Immune response; Infectious diseases; Inflammasomes; Inflammation; Isoforms; Lipopolysaccharides; Microglia; Neurodegenerative diseases; NLRP3 inflammasome; Pyroptosis; snRNA
• ISSN: 1323-1316; 1440-1819; 1440-1819
• DOI: 10.1111/pcn.13704

Background 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. Methods 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. Results 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. Conclusions 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.