APOE4 homozygotes are resistant to the mnemonic benefits of 17β-estradiol in the EFAD mouse model of Alzheimer's disease.

Abstract

Loss of circulating estrogens at menopause may contribute to increased risk for Alzheimer's disease (AD) in females relative to males. APOE4, the greatest genetic risk factor for AD, acts synergistically with estrogens to increase risk in females. However, despite the relative contributions of APOE genotype and estrogen loss to sex differences in AD risk, these factors are rarely examined in concert in basic research. Hence, our knowledge of how APOE genotype may interact with estrogens to contribute to AD risk, or whether estrogens may be of benefit to particular genotypes, is limited. The present study was designed to test whether APOE genotype interacts with E2 to modulate cognition and dendritic spine density in a mouse model of AD. Effects of 17β-estradiol (E2 ) treatment on memory were examined in ovariectomized (OVXed) transgenic mice expressing 5 familial AD mutations (5XFAD) and two copies of human APOE3 (E3FAD), APOE4 (E4FAD), or one copy each of APOE3/APOE4 (E3/4FAD). OVXed female E3FAD, E3/4FAD, and E4FAD mice received bilateral dorsal hippocampal (DH) infusion of E2 immediately after training in object recognition (OR) and object placement (OP) tasks. Next, the effect of APOE genotype to modulate estrogenic effects on spines was examined. E3FAD, E3/4FAD, and E4FAD mice received DH infusion of E2 and brains were collected for Golgi impregnation and quantification of dendritic spine density 2 h later. DH infusion of E2 facilitated OR and OP memory in E3FAD and E3/4FADs, but not E4FADs. Similarly, DH infusion of E2 increased CA1 apical dendritic spine density in E3FADs and E3/4FADs, but not E4FADs. CA1 basal spine density was significantly reduced by E4FAD genotype. The significant benefit of E2 only in E3FAD and E3/4FAD mice suggests that having two copies of the APOE4 allele results in lower susceptibility to the memory-enhancing effects of E2 in the EFAD model. These findings provide novel evidence that E2 may be of clinical benefit to APOE3 and APOE3/4, but not homozygous APOE4, carriers.