APOE4 homozygote females are resistant to the beneficial effects of 17β-estradiol on memory and CA1 dendritic spine density in the EFAD mouse model of Alzheimer's disease

Abstract

Female APOE4 carriers are at greatest risk of Alzheimer's disease (AD). The potent estrogen 17β-estradiol (E₂) may mediate AD risk, as the onset of memory decline coincides with the menopausal transition. Whether APOE genotype mediates E₂'s effects on memory and neuronal morphology is poorly understood. We used the APOE^+/+/5xFAD^+/- (EFAD) mouse model to examine how APOE3 homozygote (E3FAD), APOE3/4 heterozygote (E3/4FAD), and APOE4 homozygote (E4FAD) genotypes modulate effects of E₂ on object and spatial memory consolidation, dendritic spine density, and dorsal hippocampal estrogen receptor expression in 6-month-old ovariectomized EFAD mice. Dorsal hippocampal E₂ infusion enhanced memory consolidation and increased CA1 apical spine density in E3FAD and E3/4FAD, but not E4FAD, mice. CA1 basal mushroom spines were also increased by E₂ in E3FADs. E4FAD mice exhibited reduced CA1 and mPFC basal spine density, and increased dorsal hippocampal ERα protein, independent of E₂. Overall, E₂ benefitted hippocampal memory and structural plasticity in females bearing one or no APOE4 allele, whereas two APOE4 alleles impeded the memory-enhancing and spinogenic effects of E₂.

Keywords: 17β-estradiol; APOE4; Alzheimer's disease; Apolipoprotein E; Hippocampus; Medial prefrontal cortex; Object recognition; Spatial memory.