Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

Abstract

Alzheimer's disease ͉ estrogen therapy ͉ risk factor regulation ͉ Alzheimer's disease prevention A polipoprotein E (ApoE) is a 34-kDa lipid binding protein that functions in the transport of triglycerides and cholesterol in multiple tissues, including brain, by interacting with lipoprotein receptors on target cells (1-4). Three ApoE isoforms exist in humans: ApoE2, ApoE3, and ApoE4, which differ from one another by single amino acid substitutions at positions 112 and 158, ApoE2 (Cys-112, Cys-158), ApoE3 (Cys-112, Arg-158), and ApoE4 (Arg-112, Arg-158) (5). Substitution of cysteine at position 158 in ApoE2 results in hypocholesterolemia caused by low levels of low-density lipoprotein (LDL), cholesterol (6). In contrast, substitution of cysteine with arginine at position 112 in ApoE4 results in elevation of plasma cholesterol and LDL levels and predisposes the carrier to cardiovascular disease and neurodegenerative disorders, including Alzheimer's disease (AD) (7,8).Statistically, individuals with one copy of the ApoE4 allele show a 4-fold increase in the risk of AD, whereas those with two copies of the ApoE4 allele exhibit a 15-fold increase in risk coupled with a significantly lower age of onset compared with AD patients carrying ApoE2͞3 alleles (9). The ApoE4 allele itself appears to account for as much as 50% of the populationattributable AD risk in the United States (for reviews see refs. 10 and 11). Thus, ApoE4 is considered a risk factor for late-onset AD, whereas ApoE2 and ApoE3 are associated with decreased risk of AD (10,12,13).Previous in vitro and in vivo analyses indicate that 17␤-estradiol (E 2 ) increased ApoE expression in astrocytes and microglia and in neurons (14, 15). Further, ApoE synthesis was required for E 2 -induced neuroprotection and neurotrophism, including neurite outgrowth (16,17).Recently, we discovered that in HT-22 cells ectopically transfected with full-length estrogen receptor (ER) (ER␣ or ER␤), E 2 -induced an opposite effect on ApoE expression depending on the transfected ER subtype. Based on our own data and others (17-19), we hypothesized that ApoE expression is differentially regulated by ER subtypes. To test this hypothesis, we investigated the impact of ER␣ versus ER␤ on ApoE gene expression by using real-time RT-PCR with confirmation of protein levels by Western blot in primary cultured rat hippocampal neurons. To determine the in vivo significance of our in vitro findings, we conducted in vivo analyses in ovariectomized (OVX) female rats treated with either the ER␣-selective ligand, propylpyrazole triol (PPT) or the ER␤-selective ligand, diarylpropionitrile (DPN). Results of these analyses demonstrated that the expression of ApoE is differentially regulated by ER␣ and ER␤. Activation of ER␣ increased, whereas activation of ER␤ decreased ApoE mRNA and protein expression in vitro and in vivo in rat hippocampus. Results Differential ApoE Expression in HT-22 Cells Transfected with ER␣ orER␤. To determine the ER subtype mediating E 2 regulation of ApoE, mouse hybrid HT-22 cel...

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

“…Stone [54] and others [49;64] have shown that 17β-estradiol treatment increases the production and release of apoliporotein E from astrocytes and microglia. More recently, Wang et al [64] have shown that ERα activation is responsible for up-regulation of apolipoprotein E in HTT cells and in primary neuronal cultures while ERβ down-regulates apolipoprotein E production. Thus, the high levels of ERβ in APOE4 microglia compared to APOE3 microglia may account, at least in part, for the lower level of apolipoprotein E protein that has been observed in APOE4 mice brain [47].…”

EstradiolIn VivoRegulation of Brain Mitochondrial Proteome

“…At time of killing, uteri were removed and weighed to confirm biological efficacy of E 2 -treatment. Previous studies demonstrated that E 2 plasma and brain levels after a 30 g/kg dose produced levels in ovariectomized rats of 42 pg/g brain tissue (wet weight) E 2 in brain tissue and 44 pg/ml E 2 in serum (Wang et al, 2006).…”

The effect of hormone therapy on olfactory sensitivity is dependent on apolipoprotein E genotype

“…HT has been shown to increase the risk of AD in those with the ε4 allele and to decrease risk in those with the ε2 or ε3 allele (Kaplitt et al, 1996;Mahley et al, 2006;Saunders et al, 2000). Wang et al, 2006 suggest that an increase of ERα combined with HT will increase ApoE which would selectively increase the risk of cognitive impairment in ApoE 4 positive individuals, in a heterogeneous population in a large clinical trial.…”

“…Results from another prospective study also provided evidence of a slightly greater positive effect of HT on women with one ε4 allele (Tang et al, 1996). Wang, Irwin and Brinton (2006) have reported that estrogen receptor alpha (ERα) increases and estrogen receptor beta (ERβ) decreases ApoE expression in the hippocampus in rats. They have argued that the interaction of ε4 allele status and estrogen receptor type may partially explain the complex results in human clinical trials of HT on cognitive function.…”