Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cells

Kim, Hee; Bang, Oh Young; Jung, Min Whan; Ha, Sang Duk; Hong, Hyun Seok; Huh, Kyu Ha; Kim, Seung Up; Mook‐Jung, Inhee

doi:10.1016/s0304-3940(01)01659-7

Cited by 69 publications

(50 citation statements)

References 20 publications

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“…Nuclear staining data supported cell viability experiments, suggesting that estradiol prevents TRAILinduced apoptosis of MO3.13 cells. The beneficial effect of estradiol was specific, as the addition to the cultures of the two ER antagonists tamoxifen or ICI 187,580 at concentrations not influencing protein synthesis and known to antagonize estradiol effects in most in vitro systems, 40,41 resulted in restored cell death rate after addition of TRAIL.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

et al. 2004

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Demyelinating diseases are high impact neurological disorders. Steroids are regarded as protective molecules in the susceptibility to these diseases. Here, we studied the interactions between tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent proapoptotic molecule toxic to oligodendrocytes, and 17-b-estradiol (E-17-b), in human oligodendrocytic MO3.13 cells. Exposure of cells to TRAIL resulted in the upregulation of both death receptors DR4 and DR5 and apoptosis, as well as the activation of caspase-8 and -3, increased phosphorylation of Jun-Nterminal kinase and p38 kinase, and the reduction of bcl-2 and bcl-xL proteins. TRAIL-mediated MO3.13 cell apoptosis was abrogated by the dominant-negative form of the adaptor protein FADD and by caspase inhibitors. Preincubation with E-17-b completely prevented both TRAIL-induced DR4 and DR5 upregulation and apoptosis. Estrogen-induced cytoprotection was time and concentration dependent and reverted by antiestrogens. Estrogen treatment per se reduced kinase phosphorylation, and upregulated bcl-2 and bcl-xL proteins.In conclusion, our data show that the detrimental role of TRAIL on oligodendrocytes can be effectively counteracted by estrogens, thus suggesting that the underlying molecular interactions can be of potential relevance in characterizing novel targets for therapy of demyelinating disorders.

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Section: Discussionmentioning

confidence: 99%

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

et al. 2004

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“…It has also been reported that estrogen replacement in postmenopausal women is protective for Alzheimer's disease (42,43). Because FKHRL1 has been shown to induce cell death by apoptosis in neuronal cells (17), it is plausible that ER␣ interaction with forkhead proteins in neuronal tissue may support cell survival.…”

Section: Discussionmentioning

confidence: 99%

Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family

Schuur

Loktev

Sharma

et al. 2001

Journal of Biological Chemistry

140

126

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Estrogen acting through the estrogen receptor (ER) is able to regulate cell growth and differentiation of a variety of normal tissues and hormone-responsive tumors. Ligand-activated ER binds DNA and transactivates the promoters of estrogen target genes. In addition, ligandactivated ER can interact with other factors to alter the physiology and growth of cells. Using a yeast two-hybrid screen, we have identified an interaction between ER␣ and the proapoptotic forkhead transcription factor FKHR. The ER␣-FKHR interaction depends on ␤-estradiol and is reduced significantly in the absence of hormone or the presence of Tamoxifen. A glutathione S-transferase pull-down assay was used to confirm the interaction and localized two interaction sites, one in the forkhead domain and a second in the carboxyl terminus. The FKHR interaction was specific to ER␣ and was not detected with other ligand-activated steroid receptors. The related family members, FKHRL1 and AFX, also bound to ER␣ in the presence of ␤-estradiol. FKHR augmented ER␣ transactivation through an estrogen response element. Conversely, ER␣ repressed FKHRmediated transactivation through an insulin response sequence, and cell cycle arrest induced by FKHRL1 in MCF7 cells was abrogated by estradiol. These results suggest a novel mechanism of estrogen action that involves regulation of the proapoptotic forkhead transcription factors.Estrogen and related steroid ligands play a critical role in the normal development and function of numerous cell types. Estrogens induce physiologic effects through an interaction with nuclear steroid receptors. Two human estrogen receptors have been identified, ER␣ 1 and ER␤ (1-4). The ERs are members of the steroid-thyroid-retinoic acid superfamily of transcription factors (5). In the classic model of steroid hormone action, ␤-estradiol induces homodimerization of ER, which is able to bind specific regulatory sequences in the promoters of ER target genes called estrogen response elements (EREs) (6). It is through this classic model of steroid hormone action that ERs alter the expression of a set of target genes. Several target genes for ER␣ in hormone-responsive breast tumors have been described including progesterone receptor (PR) (7), pS2 (8), TGF-␣ (9), cathepsin D (10), HSP27 (11), and GREB1 (12). These genes are directly activated by ER␣, and the induction of gene expression depends on the ability for ER␣ to bind to the promoters of each target gene.Increasingly, it has been reported that estrogen acting through ERs can have profound effects on cell physiology through mechanisms independent of DNA binding. One mechanism that has been proposed is through the ability of ER␣ to regulate the activity of other nuclear transcription factors by mechanisms involving direct protein-protein interactions. In many cases the interactions between ER␣ and other nuclear factors have been shown to be ligand-dependent. One example of this alternate mechanism of gene regulation is the effect of ER␣ on the expression of AP1-regulated genes (13). ER␣ ...

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“…It has outstanding neuroprotective and neurotrophic activities and has been linked to neurodegenerative diseases, including Alzheimer's disease (AD) [1,2] . A large body of work has shown that estrogen can block β-amyloid peptide (Aβ)-induced neuronal cell death and influence Aβ secretion [3][4][5][6][7] . However, long-term compliance with estrogen administration is estimated to be no more than 15%-40% because of undesirable side effects [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

2009

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Aim: To examine whether liquiritigenin, a newly found agonist of selective estrogen receptor-β, has neuroprotective activity against β-amyloid peptide (Aβ) in rat hippocampal neurons. Methods: Primary cultures of rat hippocampal neurons were pretreated with liquiritigenin (0.02, 0.2, and 2 μmol/L) prior to Aβ 25-35 exposure. Following treatment, viability of the cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis and by a lactate dehydrogenase activity-based cytotoxicity assay. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) and levels of reactive oxygen species (ROS), as well as apoptotic rates, were determined. Our studies were extended in tests of whether liquiritigenin treatment could inhibit the secretion of Aβ 1-40 as measured using an ELISA method. In order to analyze which genes may be involved, we used a microarray assay to compare gene expression patterns. Finally, the levels of specific proteins related to neurotrophy and neurodenegeration were detected by Western blotting. Results: Pretreated neurons with liquiritigenin in the presence of Aβ 25-35 increased cell viability in a concentration-dependent manner. Liquiritigenin treatment also attenuated Aβ 25-35 -induced increases in [Ca 2+ ] i and ROS level and decreased the apoptotic rate of neurons. Some genes, including B-cell lymphoma/leukemia-2 (Bcl-2), neurotrophin 3 (Ntf-3) and amyloid β (A4) precursor protein-binding, family B, member 1 (Apbb-1) were regulated by liquiritigenin; similar results were shown at the protein level by Western blotting. Conclusion: Our results demonstrate that liquiritigenin exhibits neuroprotective effects against Aβ 25-35 -induced neurotoxicity and that it can decrease the secretion of Aβ 1-40 . Therefore, liquiritigenin may be useful for further study as a prodrug for treatment of Alzheimer's disease.

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Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cells

Cited by 69 publications

References 20 publications

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

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