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

Abstract

The apolipoprotein E4 (APOE4) gene is a well-known risk factor for Alzheimer's disease (AD) and other neurological disorders. Post-menopausal women with AD who express at least one APOE4 gene have more severe neuropathology and worsened cognitive scores than their non-expressing counterparts. Since 17β-estradiol down-regulates inflammation as part of its neuroprotective role, we examined the effect of 17β-estradiol on the response of microglia to immune activation as a function of APOE genotype. Our data show that the anti-inflammatory activity of 17β-estradiol is significantly reduced in APOE4 targeted replacement mice compared to APOE3 mice. A significant interaction between APOE genotype and the response to 17β-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 17β-estradiol responsiveness. ERβ protein levels in APOE4 microglia were higher than APOE3 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 17β-estradiol's action and may impact the neuroprotective role of 17β-estradiol and of hormone replacement therapy on brain function when the APOE4 gene is expressed.

APOE epsilon‐4 allele and cytokine production in Alzheimer's disease

“…How the APOE gene influences PBMC activity was not investigated, since the levels of apolipoprotein E produced during PBMC incubation (12 h þ 4 h for PMA-stimulated cells) were not detected. Nevertheless, prior to ours, animal studies have displayed APOE-dependent variations in morphology and function in microglia cells and peripheral macrophages (Vitek et al, 2007;Brown et al, 2008). In addition a significant increase in cell apoptosis was reported in lymphocytes from AD patients bearing one or two alleles of the APOE4 compared to non-E4 carriers (Frey et al, 2006).…”

Deficiency of CARD8 Is Associated with Increased Alzheimer’s Disease Risk in Women

“…Following intracerebroventricular injection of LPS, microglial and NF-B activation are more pronounced in the hippocampi of transgenic ApoE4 than in ApoE3 mice [8] . In addition, ApoE genotype may alter the neuroprotective role of 17 ␤ -estradiol on brain function, with the anti-inflammatory activity of 17 ␤ -estradiol being reduced in ApoE4 mice [13] . These data in mouse models could be translated to the human population, and then the presence of the ApoE 4 allele might exacerbate the inflammatory events linked to women carrying the CARD8 A allele.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…The two ER proteins recognised so far, ERa and ERb, are intracellular proteins which activate genomic as well as nongenomic effectors in neural cells [145]. Through the use of the estrogen receptor antagonist ICI 182780 we and others initially ascribed hormone action in microglia to the activation of endogenous ERs, since this molecule was able to block the effect of estradiol ( [24,25,141,241]). Using ER-null mice several reports described the selective involvement of ERa in the anti-inflammatory and neuroprotective activity of estradiol against neuroinflammatory and vascular pathologies of the brain ( [62,80,185,242]).…”