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Published on: December 26, 2016
Synergism of ApoE4 and systemic infectious burden is mediated by the APOE-NLRP3 axis in Alzheimer's disease
Xue-Ting Liu1, Xiu Chen1, Na Zhao1
1School of Medicine, Southeast University, Nanjing, China.
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.
Insights
The APOE4 gene variant exacerbates microglia inflammation via the NLRP3 inflammasome pathway, increasing Alzheimer's disease (AD) risk after infections. Targeting NLRP3 may offer therapeutic strategies for AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Systemic infections increase Alzheimer's disease (AD) risk, particularly in APOE4 carriers.
- The precise mechanism of APOE4's influence on microglia-driven inflammation is not fully understood.
Purpose of the Study:
- To elucidate the role of APOE4 in microglia inflammatory responses during systemic infections.
- To investigate the involvement of the NLRP3 inflammasome pathway in APOE4-mediated neuroinflammation.
Main Methods:
- Analyzed human snRNA-seq data to identify differentially expressed genes (DEGs) in microglia between APOE3 and APOE4.
- Stimulated in vitro and in vivo models with ApoE in the presence/absence of LPS or ATP.
- Utilized NLRP3 gene knockout experiments and biochemical analyses to assess inflammation and mitochondrial autophagy.
Main Results:
- APOE4 up-regulated pro-inflammatory genes in microglia compared to APOE3.
- ApoE4 stimulation increased NLRP3 inflammasomes and reactive oxygen species (ROS) in microglia.
- APOE4 combined with LPS/ATP promoted pyroptosis, NF-κB activation, and mitochondrial autophagy dysfunction, effects reversed by NLRP3 knockout.
Conclusions:
- NLRP3 inflammasomes are crucial in linking APOE4 to microglia immune function.
- Findings provide a molecular basis for APOE4-associated neuroinflammation and increased AD risk post-infection.
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