The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol

The apolipoprotein E4 (APOE4) gene is a well-known risk factor for Alzheimer's disease (AD) and other neurological disorders. Postmenopausal women with AD who express at least one APOE4 gene have more severe neuropathology and worsened cognitive scores than their non-expressing counterparts. Since 17 beta-estradiol down-regulates inflammation as part of its neuroprotective role, we examined the effect of 17 beta-estradiol on the response of microglia to immune activation as a function of APOE genotype. Our data show that the anti-inflammatory activity of 17 beta-estradiol is significantly reduced in APOE4 targeted replacement mice compared to APOE3 mice. A significant interaction between APOE genotype and the response to 17 beta-estradiol was observed for NO and cytokine production by immune activated microglia. The genotype specific effect was not restricted to brain macrophages since peritoneal macrophages from APOE4 ovariectomized mice also demonstrated a significant difference in 17 beta-estradiol responsiveness. ER beta protein levels in APOE4 microglia were higher than APOE-3 microglia, suggesting a difference in post-translational protein regulation in the presence of the APOE4 gene. Overall, our data indicate that the APOE genotype may be a critical component in assessing the effectiveness of 17 beta-estradiol's action and may impact the neuroprotective role of 17 beta-estradiol and of hormone replacement therapy on brain function when the APOE4 gene is expressed. (c) 2007 Elsevier Inc. All rights reserved.