Why is the APOEε2 variant of the APOE gene associated with a lower risk of Alzheimer’s disease and slightly longer life expectancy? Past research has investigated the role of APOE in cholesterol metabolism and inflammation in microglia, the innate immune cells of the brain implicated in neurodegenerative conditions. Here, researchers focus instead on pericytes and their role in maintaining the blood-brain barrier. The barrier prevents unwanted molecules and cells from entering the brain, but becomes leaky with age. This leakage of the blood-brain barrier generates inflammation and damage in the brain, and is thought to be an early inciting event in the onset of neurodegenerative conditions.
Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer’s disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity.
To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation.
Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated lipid droplet accumulation in APOE3 and APOE4 pericytes.
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