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ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.
Biorxiv : the Preprint Server for Biology
|May 18, 2026
Summary
Apolipoprotein E4 (ApoE4) increases Alzheimer's disease risk. Lipid-bound ApoE4 alters microglial metabolism, while lipid-free ApoE4 triggers inflammation, revealing lipidation's role in ApoE4's effects.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD).
- ApoE4's impact on microglial metabolism and function is implicated in AD pathogenesis.
- The role of ApoE lipidation status in ApoE4-induced microglial dysfunction is unclear.
Purpose of the Study:
- To investigate the effects of ApoE isoform and lipidation state on human microglial metabolism and phenotype.
- To determine how lipid-bound versus lipid-free ApoE4 influences microglial function.
Main Methods:
- Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4.
- Label-free live-cell holotomography assessed lipid droplet dynamics and mitochondrial morphology.
- Global proteomics analyzed microglial phenotype and signaling pathways.
Main Results:
- ApoE4 treatment led to enlarged lipid droplets and mitochondrial fragmentation compared to ApoE3.
- Lipid-bound ApoE4 exacerbated these effects.
- Lipid-free ApoE, particularly ApoE4, induced a strong type I interferon response.
Conclusions:
- Lipid-bound ApoE4 drives metabolic changes in microglia.
- Lipid-free ApoE4 promotes inflammatory signaling.
- ApoE lipidation is a critical factor modulating ApoE4's contribution to Alzheimer's disease risk.
