Abstract
Introduction: Alzheimer's disease (AD) is characterized by tau pathology, leading to neurodegeneration. Astrocytes regulate central nervous system homeostasis and influence AD progression. The APOE3-Christchurch (APOE3-Ch) variant is linked to AD resilience, but its protective mechanisms remain unclear. Methods: Human induced pluripotent stem cell-derived astrocytes (APOE3-Ch and wild type) were used to assess tau uptake, clearance, lipid metabolism, and transcriptomic adaptations. Fluorescently labeled 2N4R-P301L tau oligomers were tracked, and pathway-specific inhibitors dissected tau clearance mechanisms. Lipidomic and transcriptomic analyses were performed to identify genotype-specific adaptations. Results: APOE3-Ch astrocytes exhibited enhanced tau uptake via heparan sulfate proteoglycan- and lipoprotein receptor-related protein 1-mediated pathways and superior clearance through lysosomal and proteasomal degradation. They exported less tau, limiting propagation. Transcriptomic analyses revealed upregulation of genes involved in cell projection assembly and endocytosis. Lipidomic profiling showed reduced ceramides and gamma-linolenic acid, linked to decreased neuroinflammation and ferroptosis. Discussion: APOE3-Ch astrocytes promote tau clearance and metabolic adaptations, providing insights into genetic resilience in AD and potential therapeutic targets. Highlights: APOE3-Christchurch (APOE3-Ch) astrocytes exhibit significantly increased tau internalization compared to wild-type astrocytes, facilitated by upregulated heparan sulfate proteoglycan and low-density lipoprotein receptor-related protein 1 pathways. APOE3-Ch astrocytes demonstrate more efficient tau degradation via both lysosomal and proteasomal pathways, while exporting significantly less tau, potentially reducing tau propagation in the central nervous system. APOE3-Ch astrocytes show upregulation of genes involved in cell projection assembly and endocytosis, suggesting structural and functional modifications that enhance tau processing. Lipidomic profiling reveals reduced ceramide levels and gamma-linolenic acid downregulation in APOE3-Ch astrocytes, alterations linked to reduced neuroinflammatory and ferroptotic activity, contributing to the protective phenotype.