Alzheimer's Disease Risk Allele APOE4 Interacts with Arsenic Exposure to Drive Microglial Dysfunction

Area of Science:

• Neuroscience
• Genetics
• Toxicology

Background:

• Alzheimer's disease (AD) pathogenesis involves genetic risk and environmental factors.
• The role of gene-environment interactions in human microglia, the brain's immune cells, is not well understood.
• The apolipoprotein E4 (APOE4) allele is a significant genetic risk factor for late-onset AD.

Purpose of the Study:

• To investigate if the APOE4 allele increases microglial vulnerability to environmental exposures, specifically arsenite.
• To explore the molecular mechanisms underlying APOE4-mediated microglial responses to toxicants.

Main Methods:

• Generated isogenic human induced microglia-like cells (iTFM) with APOE4/APOE4 or APOE3/APOE3 genotypes using CRISPR/Cas9.
• Exposed iTFM to arsenite and assessed cell survival (LC50).
• Performed transcriptomic profiling and weighted gene co-expression network analysis (WGCNA).
• Conducted functional assays to evaluate phagocytosis and mitochondrial function.

Main Results:

• APOE4/APOE4 iTFM showed decreased survival and a lower LC50 upon arsenite exposure compared to APOE3/APOE3 controls.
• Transcriptomic analysis revealed arsenite as the primary driver of gene expression, with genotype contributing a distinct secondary response.
• Genotype-dependent WGCNA modules were enriched for phagocytic and oxidative stress pathways (e.g., KEAP1-NFE2L2 signaling).
• APOE4/APOE4 iTFM exhibited altered mitochondrial phenotypes (increased mass, reduced membrane potential, decreased superoxide production) that were exacerbated by arsenite.

Conclusions:

• A gene-environment interaction, specifically APOE4 and arsenite exposure, increases microglial vulnerability.
• This interaction reshapes transcriptional and functional stress responses in microglia.
• Provides a human cell model for studying environmentally mediated microglial roles in AD.