Estrogen Facilitates Neurite Extension via Apolipoprotein E in Cultured Adult Mouse Cortical Neurons

Nathan, Britto P.; Barsukova, Anna; Shen, Fei; McAsey, Mary E.; Struble, Robert G.

doi:10.1210/en.2003-1707

Cited by 84 publications

(81 citation statements)

References 53 publications

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“…These findings are consistent with previous reports of Finch and colleagues (15) who demonstrated that E 2 increased ApoE in cells isolated from CNS and by other investigators in vivo (16)(17)(18). In this study, we demonstrated that ApoE expression is differentially regulated by ER␣ and ER␤.…”

Section: Discussionsupporting

confidence: 94%

“…E 2 had no effect on neurite outgrowth in neuron cultures from mice lacking the ApoE gene or mice transgenic for human ApoE4. In contrast, E 2 significantly increased neurite growth of neurons in culture from mice transgenic for human ApoE3 (16). Although the ApoE2͞3 and ApoE4 genotypes responded differently to E 2 -induced neuritic sprouting, E 2 induced an increase in ApoE expression regardless of genotype (16).…”

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 87%

“…In the absence of ApoE, estrogen did not show any effect on neurite sprouting (42,43). Nathan et al (16) found that E 2 -induced neurite sprouting depended on the ApoE genotype. ApoE4 inhibited, whereas ApoE3 enhanced, neurite outgrowth in a dose-dependent manner (44,45).…”

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 94%

“…Several groups have demonstrated that estrogen regulates ApoE expression (14)(15)(16)(17). In vivo verification of in vitro E 2 regulation of ApoE was demonstrated in the study by Struble et al (17).…”

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 97%

“…Further, ApoE synthesis was required for E 2 -induced neuroprotection and neurotrophism, including neurite outgrowth (16,17).…”

mentioning

confidence: 99%

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

Wang

Irwin

Brinton

2006

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 94%

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 87%

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 94%

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 97%

“…Further, ApoE synthesis was required for E 2 -induced neuroprotection and neurotrophism, including neurite outgrowth (16,17).…”

mentioning

confidence: 99%

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

Wang

Irwin

Brinton

2006

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease, estrogens, and clinical trials: a case study in drug development for complex disorders

Howell

Dykens²,

Moos

2005

Drug Development Research

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting more than 4 million Americans, and it is a huge drain on health care resources. Moreover, the cost burden of AD will increase substantially without the development of drugs that prevent its onset or slow its progression. At the present time, the available AD drugs provide, at best, temporary cognitive improvement, and costbenefit analyses indicate no more than marginal support for their use. AD is a disorder of complex etiology that is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain. The Amyloid Cascade model of AD neurodegeneration postulates that the primary disease process is the deposition of amyloid plaques and their subsequent effects on cognition. However, as we review here, the emerging evidence argues against simple linear models of neurodegeneration in AD patients, and more complex models of etiology and pathogenesis are needed as part of the drug development process. As one potential therapeutic approach, there is substantial evidence that estrogens are neuroprotective and act on a number of neural pathways, many of which are compromised in AD. A number of studies have shown that estrogens provide clinical benefit in AD patients and in other neurodegenerative disorders. Unfortunately, the negative results of the Women's Health Initiative Memory Study (WHIMS) have overshadowed the positive results from the last four decades. However, as discussed here, there are a number of reasons why the WHIMS results should not be generalized. On balance, estrogens remain a fruitful drug development approach for AD, and other neurodegenerative conditions, and especially those estrogen compounds or analogues that avoid or minimize the complications associated with long-term use of feminizing hormones in post-menopausal women. Drug Dev. Res. 66:53-77, 2006.

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Estrogen receptor β as a therapeutic target for promoting neurogenesis and preventing neurodegeneration

Zhao

Brinton

2005

Drug Development Research

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Both estrogen receptor (ER) subtypes, ERa and ERb, are expressed throughout the brain of both rodents and humans. Analyses from our laboratory and others reveal that both ERa and ERb can contribute to estrogen-induced protection against neurodegenerative insults. ERb plays a key role in regulating brain development and estrogen-induced promotion of neurogenesis and memory. These findings suggest that targeting ERb could generate safe and effective therapeutics to promote neuronal defense mechanisms and to maintain cognitive function, while simultaneously reducing adverse effects in reproductive organs such as breast and uterus. A number of naturally occurring ERb selective phytoestrogens have been identified and multiple structurally diverse ERb selective ligands have been synthesized. A comparison of the models of complexes between selective agonists and either ERa or ERb reveals that two variant amino acid residues in the ligand binding site, Leu384 and Met421 in ERa, which are replaced with Met336 and Ile373, respectively, in ERb, are the key molecular constituents underlying the binding of selective ligands to either ER subtype. Development of an ERb brain-selective estrogen receptor modulator, in particular a natural source formulation, has great potential benefit for peri-and post-menopausal women who face age-associated cognitive decline and neurodegeneration. In addition, an ERb selective formulation might promote neuronal defense mechanisms and cognition in men, while reducing the risk of prostate cancer. Drug Dev.The profound disparities between the largely positive basic science findings of estrogen action in the brain [see the recent reviews of Brinton, 2004a,b;Simpkins et al., 2005] and the adverse outcomes of recent estrogen therapy (ET) trials in women who are either postmenopausal and normal Shumaker et al., 2003Shumaker et al., , 2004Espeland et al., 2004] or postmenopausal with Alzheimer's disease DDR Published online in Wiley InterScience (www.interscience.wiley. com).

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Estrogen Facilitates Neurite Extension via Apolipoprotein E in Cultured Adult Mouse Cortical Neurons

Cited by 84 publications

References 53 publications

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

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

Alzheimer's disease, estrogens, and clinical trials: a case study in drug development for complex disorders

Estrogen receptor β as a therapeutic target for promoting neurogenesis and preventing neurodegeneration

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