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Estrogen receptor-mediated neuroprotection: The role of the Alzheimer's disease-related gene seladin-1.

Peri A, Serio M - Neuropsychiatr Dis Treat (2008)

Bottom Line: Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against beta-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis.Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen.This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Physiopathology, Endocrine Unit, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence Florence, Italy.

ABSTRACT
Experimental evidence supports a protective role of estrogen in the brain. According to the fact that Alzheimer's disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. However, there is no general consensus on the beneficial effect of estrogen or selective estrogen receptor modulators in preventing or treating AD. It has to be said that several factors may markedly affect the efficacy of the treatment. A few years ago, the seladin-1 gene (for selective Alzheimer's disease indicator-1) has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against beta-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis. Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen. Furthermore, our very recent data support the hypothesis that seladin-1 is a mediator of the neuroprotective effects of estrogen. This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.

No MeSH data available.


Related in: MedlinePlus

Amount of seladin-1 mRNA, assessed by real-time RT-PCR, in untreated control FNC cells (C), in cells treated with 1 nM 17β-estradiol (17βE2), 1 nM tamoxifen (TMX) or raloxifene (Ral) (1–100 nM).Notes: *p < 0.05 vs control cells (C) value (112 ± 2.26 fg/μg total RNA, mean ± SE), considered as 100%. Modified with permission from Benvenuti S, Luciani P, Vannelli GB, et al 2005. Estrogen and SERMs exert neuroprotective effects and stimulate the expression of seladin-1, a recently discovered anti-apoptotic gene, in human neuroblast long-term cell cultures. J Clin Endocrinol Metab, 90:1775–82.
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fig3: Amount of seladin-1 mRNA, assessed by real-time RT-PCR, in untreated control FNC cells (C), in cells treated with 1 nM 17β-estradiol (17βE2), 1 nM tamoxifen (TMX) or raloxifene (Ral) (1–100 nM).Notes: *p < 0.05 vs control cells (C) value (112 ± 2.26 fg/μg total RNA, mean ± SE), considered as 100%. Modified with permission from Benvenuti S, Luciani P, Vannelli GB, et al 2005. Estrogen and SERMs exert neuroprotective effects and stimulate the expression of seladin-1, a recently discovered anti-apoptotic gene, in human neuroblast long-term cell cultures. J Clin Endocrinol Metab, 90:1775–82.

Mentions: Finally, in order to answer the question whether estrogen and/or SERMs have an effect on seladin-1 expression, we evaluated the expression of seladin-1 mRNA in FNC cells, treated or not with 17β-estradiol, tamoxifen or raloxifene, by quantitative real-time RT-PCR based on TaqMan technologies. We found that FNC cells constitutively express seladin-1 (112 ± 2.26 fg/μg total RNA, mean ± SE). Noticeably, 17β-estradiol (10 pM–100 nM) significantly increased the amount of seladin-1 mRNA. 1 nM tamoxifen or raloxifene determined a similar increase of seladin-1 mRNA, compared to an equal concentration of 17β-estradiol. However, higher concentrations of raloxifene (10–100 nM) determined a marked reduction of seladin-1 expression, in keeping with the observed lack of a neuroprotective effect at these concentrations (Figure 3). The effect of a selective ERα (propylpyrazole-triol, PPT) or a selective ERβ (diarylpropionitrile, DPN) agonist was also tested. We found that PPT determined a significant increase of the amount of seladin-1 mRNA at a concentration (10 nM) which has been reported to induce evident transcriptional activity (Harrington et al 2003), whereas DPN produced a weaker effect. These additional findings suggested a predominant role of ERα in mediating the stimulatory effect of estrogen on seladin-1 expression. In conclusion, this study led us to hypothesize that seladin-1 might be a mediator of the neuroprotective effects of estrogen/SERMs. In particular, the parallelism between the concentrations of raloxifene that conferred neuroprotection on one hand, and stimulated seladin-1 expression on the other hand, was highly predictive that this was true.


Estrogen receptor-mediated neuroprotection: The role of the Alzheimer's disease-related gene seladin-1.

Peri A, Serio M - Neuropsychiatr Dis Treat (2008)

Amount of seladin-1 mRNA, assessed by real-time RT-PCR, in untreated control FNC cells (C), in cells treated with 1 nM 17β-estradiol (17βE2), 1 nM tamoxifen (TMX) or raloxifene (Ral) (1–100 nM).Notes: *p < 0.05 vs control cells (C) value (112 ± 2.26 fg/μg total RNA, mean ± SE), considered as 100%. Modified with permission from Benvenuti S, Luciani P, Vannelli GB, et al 2005. Estrogen and SERMs exert neuroprotective effects and stimulate the expression of seladin-1, a recently discovered anti-apoptotic gene, in human neuroblast long-term cell cultures. J Clin Endocrinol Metab, 90:1775–82.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2536547&req=5

fig3: Amount of seladin-1 mRNA, assessed by real-time RT-PCR, in untreated control FNC cells (C), in cells treated with 1 nM 17β-estradiol (17βE2), 1 nM tamoxifen (TMX) or raloxifene (Ral) (1–100 nM).Notes: *p < 0.05 vs control cells (C) value (112 ± 2.26 fg/μg total RNA, mean ± SE), considered as 100%. Modified with permission from Benvenuti S, Luciani P, Vannelli GB, et al 2005. Estrogen and SERMs exert neuroprotective effects and stimulate the expression of seladin-1, a recently discovered anti-apoptotic gene, in human neuroblast long-term cell cultures. J Clin Endocrinol Metab, 90:1775–82.
Mentions: Finally, in order to answer the question whether estrogen and/or SERMs have an effect on seladin-1 expression, we evaluated the expression of seladin-1 mRNA in FNC cells, treated or not with 17β-estradiol, tamoxifen or raloxifene, by quantitative real-time RT-PCR based on TaqMan technologies. We found that FNC cells constitutively express seladin-1 (112 ± 2.26 fg/μg total RNA, mean ± SE). Noticeably, 17β-estradiol (10 pM–100 nM) significantly increased the amount of seladin-1 mRNA. 1 nM tamoxifen or raloxifene determined a similar increase of seladin-1 mRNA, compared to an equal concentration of 17β-estradiol. However, higher concentrations of raloxifene (10–100 nM) determined a marked reduction of seladin-1 expression, in keeping with the observed lack of a neuroprotective effect at these concentrations (Figure 3). The effect of a selective ERα (propylpyrazole-triol, PPT) or a selective ERβ (diarylpropionitrile, DPN) agonist was also tested. We found that PPT determined a significant increase of the amount of seladin-1 mRNA at a concentration (10 nM) which has been reported to induce evident transcriptional activity (Harrington et al 2003), whereas DPN produced a weaker effect. These additional findings suggested a predominant role of ERα in mediating the stimulatory effect of estrogen on seladin-1 expression. In conclusion, this study led us to hypothesize that seladin-1 might be a mediator of the neuroprotective effects of estrogen/SERMs. In particular, the parallelism between the concentrations of raloxifene that conferred neuroprotection on one hand, and stimulated seladin-1 expression on the other hand, was highly predictive that this was true.

Bottom Line: Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against beta-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis.Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen.This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Physiopathology, Endocrine Unit, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence Florence, Italy.

ABSTRACT
Experimental evidence supports a protective role of estrogen in the brain. According to the fact that Alzheimer's disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. However, there is no general consensus on the beneficial effect of estrogen or selective estrogen receptor modulators in preventing or treating AD. It has to be said that several factors may markedly affect the efficacy of the treatment. A few years ago, the seladin-1 gene (for selective Alzheimer's disease indicator-1) has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against beta-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis. Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen. Furthermore, our very recent data support the hypothesis that seladin-1 is a mediator of the neuroprotective effects of estrogen. This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.

No MeSH data available.


Related in: MedlinePlus