Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• The Apolipoprotein E (APOE) gene is the primary genetic risk factor for Alzheimer's disease (AD).
• Microglia, the brain's immune cells, integrate lipid metabolism and immune regulation pathways, influenced by APOE.
• The precise role of ApoE in fundamental human microglial functions remains unclear.

Purpose of the Study:

• To investigate the impact of Apolipoprotein E (ApoE) on human microglial cellular and molecular functions.
• To characterize the phenotypes of APOE-deficient human microglia.

Main Methods:

• Generated APOE knockout (KO) microglia from Alzheimer's disease patient-derived induced pluripotent stem cells (iPSCs).
• Performed comprehensive characterization of cellular and molecular phenotypes, including transcriptomic analysis.

Main Results:

• APOE ablation led to significant lipid droplet accumulation and increased NLRP3 inflammasome activation.
• Transcriptomic data revealed downregulated cell cycle pathways and enriched oxidative stress pathways.
• APOE KO microglia showed elevated reactive oxygen species (ROS) and reduced proliferative capacity.

Conclusions:

• ApoE is a critical regulator of human microglial proliferation and function.
• Dysregulation of ApoE impacts microglial lipid metabolism, inflammation, and oxidative stress.
• These findings suggest ApoE's role in maintaining brain immune homeostasis and its implications for neurodegenerative disease pathogenesis.