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Estrogen Signaling and the Aging Context-Dependent Considerations for Postmenopausal Therapy

Department of Cell and Physiology, Loyola University Stritch School of Medicine, S First Avenue, Maywood, IL USA

Received 12 April 2013; 21 May 2013

Academic Editors: H. Galbo, E. Hajduch, M. Hiriart, and H. Ueshiba

Copyright © 2013 N. Mott and Toni R. Pak. is an open access article under the Creative Commons License. which permits use, distribution, and reproduction in any provided the original work is cited.


Recent studies have spurred debate about the benefits of therapy (HT) for postmenopausal Controversy first emerged on a sharp increase in the risk of disease in participants of the Women#x2019;s Initiative (WHI) studies, that decades of empirical in animal models was not necessarily to humans. However, a reexamination of the from the WHI studies suggests the timing of HT might be a critical and that advanced age and/or of estrogen deprivation might the body’s ability to respond to Dichotomous estrogenic effects are primarily by the actions of two high-affinity receptors alpha and beta (ER #x26; ER #x3b2; ). The expression of the ERs can be or distinct, dependent upon region, sex, age, and to hormone, and, during the of menopause, there may be changes in expression profiles, post-translational and protein:protein interactions that lead to a completely different for E 2 to exert its effects. In this factors affecting estrogen-signaling will be discussed with attention paid to the expression and actions of ER #x3b2; in brain that regulate cognition and

1. Introduction

According to the CDC (2008), the lifespan for women in the USA is #x7e;81 of age. While the average has been steadily increasing the past century (#x7e;48 in 1900), the average age at which senescence, menopause, occurs has relatively constant between years of age [1. 2 ]. Including the prepubescent this leaves women about half of their without high levels of ovarian hormones. The two primary hormones are 17 #x3b2; -estradiol (E 2 ) and both of which are required for reproduction. Many positive experiences are reported during in the reproductive cycle when E 2 is sparking further investigation the role of E 2 in various nonreproductive including those pertaining to and mood. The vast majority of science studies have positive effects of E 2 on cognitive at a molecular level, and, older postmenopausal females significant deficits when tasks that require the use of memory, attentional processing, and function [3 #x2013;8 ]. The natural process is coincident with which confounds studies to differentiate between the molecular specific to menopause versus Therefore, studies examining the and molecular functions of estrogen during periods of estrogen with respect to natural are requisite to understanding how reintroducing in aged postmenopausal women affect neurological processes. In of the wealth of studies investigating the of HT on relevant health concerns, are still very few conclusive for or against HT to ameliorate neurological Moreover, it is very likely the actions of estrogens regulate processes depending upon region and genetic composition of involved, creating complex regarding the lack of specificity of E 2 Nevertheless, some insight general functions of E 2 in the brain can be from existing data demonstrate that (1) there is a window of time surrounding for which HT can be beneficial, suggesting aging is an important factor, (2) are not likely to be beneficial for cognitive and neurological issues, and (3) the type of used may be crucial. Given important conclusions, this will focus on the molecular of E 2 signaling in the brain and how variables might contribute to these patterns can be altered by age.

2. The Menopausal Transition: E 2 Decline and Concerns

Menopause is defined by the Clinic as #x201c;the permanent end of and fertility, occurring 12 months your last menstrual Menopause is marked by a reduced number attributable to progressive of ovarian follicles and by declining levels of E 2 and progestins. The perimenopausal is typically 4#x2013;8 years, which most women symptoms including hot flushes, sweats, mood swings, disturbances, vaginal dryness and as well as urinary incontinence, of which are alleviated by hormone (E 2 ) therapy (HT/ET). Until a great deal of evidence that estrogens have effects on cognition, neuroprotection, anxiety, depression, as well as and cardiovascular health [5. 9 #x2013;13 ].

The studies to present negative of HT were the Women#x2019;s Health (WHI) and the ancillary studies the Women#x2019;s Health Initiative on Cognitive Aging (WHISCA) and the Health Initiative Memory (WHIMS). Data from studies showed that a therapy of conjugated equine acetate (CEE/MPA) increased for mild cognitive impairment and global cognitive functioning, but CEE did not have any significant effect on functioning [14 #x2013;16 ]. Poststudy have revealed many factors in the WHI studies ranging the choice of a reference group to the age of and the choice of ET used (CEE) [4. 17. 18 ], as as the use of MPA, which has been to have adverse effects on after one dose in adulthood [19 ]. the WHI studies showed negative or effects of estrogen therapy, other basic science and studies have shown the opposite. The Kronos Early Prevention Study (KEEPS) announced findings that that E 2 therapy had a positive on mood and memory. Participants CEE showed significant improvement in of depression, anxiety, and a trend reduced feelings of anger/hostility. CEE treatment or Premarin (Wyeth-Ayerst, PA, USA) is a mixture of several compounds, but primarily estrone and ring B unsaturated estrogens as equilin and equilenin, which can activate ER isoforms as compared to E 2 [20 ]. Participants receiving CEE self-reported a toward better recall of materials as compared to placebo, and using transdermal E 2 tended to fewer memory-related complaints. study performed a meta-analysis of 36 HT clinical trials (RCT) on cognition [21 ]. The length of treatment, of memory, variety of hormone, and age of the were all variables that altered the outcomes of each Results from the meta-analysis that verbal memory was often affected by HT, and younger tended to have a better in this category. There was a trend toward worse on memory tests in patients with CEE treatment alone to those treated with identical E 2 . Moreover, treatment estrogens alone (i.e. cotreatment with progestins) was associated with positive on memory tests. In conclusion, from these clinical have revealed the importance of bioidentical hormones for HT and that signaling processes for memory and can be affected by the choice of estrogen combination of hormones used as

3. Estrogen Receptor Signaling

signaling is mediated primarily two receptors (ER #x3b1; and ER #x3b2; ). ERs are I members of the nuclear hormone of receptors, deemed as a ligand-inducible factors [22 ]. Classically, ERs were to be localized in the cytoplasm bound to chaperone proteins until by ligand to translocate to the nucleus, to the two-step hypothesis coined by et al. [23 ]. Following ligand binding, ERs a conformational change that for dimerization, translocation to the nucleus, and DNA or association with other factors to regulate gene however, we now know that ER is much more complex.

For example, ERs are involved in other molecular functions including RNA second-messenger signaling cascades, and dendritic spine formation in Of particular importance in the brain, the of rapid signaling processes E 2 as a neuromodulator; however, local of E 2 has been the subject of fervent While it is likely that is de novo synthesis of E 2 within the due to technical challenges, the exact and changes with age and circulating have yet to be identified [24. 25 ]. It is difficult to determine how local E 2 may ER action. Most reports an implicit role for local E 2 at the and membrane [26 ], but whether nuclear/genomic of ERs are affected has yet to be established. Recent from our laboratory demonstrate E 2 can alter miRNA-expression [27 ], and from have shown that ER can associate with miRNA enzymes such as Drosha [28 ]. from our laboratory (unpublished and others have shown ERs are involved in alternative splicing and one study has demonstrated direct of phosphorylated ER #x3b1; with factor (SF) 3a p120 potentiates alternative splicing EGF/E 2 crosstalk [29 ]. These novel ER functions may be explained by well-studied components of classic NR such as the structural properties of the

4. Structural Contributions to ER Activity

I nuclear receptors (NRs) ER #x3b1; and ER #x3b2; have a structure comprised of five domains labeled A#x2013;E, and a domain (F) unique to ERs (Figure 1 ). The A/B contains an activator function-1-(AF-1-) domain that allows for with coregulatory proteins and transcription factors. Notably, the A/B is the least conserved domain ER #x3b1; and ER #x3b2; (17#x25; and it may be responsible for the observed ligand-independent of ER #x3b2; [30 ]. The C domain, is a DNA-binding that allows the receptor to a specific DNA sequence called an Response Element (ERE) to transcription of genes containing sequence within their region. Two zinc fingers a helix-loop-helix structure allow for spacing (3 nucleotides) between an hexameric palindromic repeat is described as the canonical ERE. The nucleotide sequence of hormone elements can vary and in part, the affinity an NR has to regulate a particular [31 ]. The D domain is a hinge-like region allows the receptor to undergo a change once activated and contains a nuclear localization The best-studied region of ERs is the E domain, referred to as the ligand-binding domain Characterization using X-ray has shown that the LBD consists of 12 alpha-helices that are essential for ligand specificity [32 ]. The orientation of 12 is critical to the conformation NRs adopt bound to a particular type of and ultimately influence the ability of the to bind other proteins and gene transcription. Helix 12 the core residues of the activator (AF-2) domain, a short conserved alpha-helix that with coregulatory proteins an LxxLL motif. Adjacent to the domain is the less characterized F that is unique to ERs. ER has a larger F domain than ER . and the two receptors only share 18#x25; homology within region. ER #x3b1; dimerization and with coregulators are altered the F domain is deleted or modified, that the F domain is a relevant for ER #x3b1; transcriptional regulation, but a role for this domain for ER has yet to be determined [33. 34 ]. Importantly, occurring human ER #x3b2; variants have altered E and F which can affect hormone in tissues that express variants.

Figure 1: Representative of domains within human and rat ER splice variants. Human ER splice variants (a) contain and changes in amino acid in the C-terminus E and F domains. Rat ER #x3b2; variants (b) contain an 18-amino-acid in the LBD/E domain and/or 3/4 exclusions in the DNA-binding domain.

The principal determinant of E 2 action is the of ER #x3b1; . ER #x3b2; . their spliced variants, or some of each, which is cell-type even within distinct nuclei. ER expression has been extensively, yet there are few definitive that can be made about the of ER #x3b2; expression. It can be noted ER expression profiles can vary the life-span, in particular when are dramatic changes in circulating levels, such as puberty and (Figure 2 ). Not only can ER expression dependent upon sex, and E 2 treatment, but these factors can direct subcellular localization, ultimately dictates ER functions. contextual studies that map the cellular expression patterns of receptor and their splice are a critical first step in a comprehensive examination of E 2 -regulated in any system.

Figure 2: Timeline factors affecting ER gene throughout the female life-span. ER gene expression patterns are with age, sex, and to circulating hormone. Circulating fluctuate with age, dramatically at the time of puberty and therefore contributing to changes in ER expression. Additionally, alternative increases with age, potentially diversifying the ER gene profile.

The female vertebrate organs tend to be dominated by the of ER #x3b1; . whereas ER #x3b2; is largely in nonreproductive tissues. ER was first cloned from tissue [42 ], and it has since been to have the highest levels of in the central nervous system and tissue, as well as lung, colorectal tissue, mammary and the immune system [43 ]. Consequently, of the most prominent phenotypic observed in mice lacking a ESR2 gene ( #x3b2; mice) are neurological deficits. By ER #x3b1; knockout mice no gross brain-related phenotypes, but exhibit decreased E 2 -mediated following an ischemic event [44 ]. the phenotypes observed in ER #x3b1; and ER #x3b2; -null mouse suggest that ER #x3b2; is more important for mediating E 2 -governed processes than ER .

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ER #x3b1; and ER #x3b2; are coexpressed in regions of the hypothalamus, such as the amygdala (MeA), the bed nucleus of the terminalis (BNST), and the periaqueductal area. However, ER #x3b1; is in hypothalamic nuclei that reproduction, sexual behavior, and (e.g. arcuate (ARC), preoptic (MPoA), and ventromedial but ER #x3b2; is the predominant isoform in the associated nuclei (e.g. (PVN), supraoptic (SON), and (SCN)) as well as the hippocampus, raphe nuclei, cortex, and [45. 46 ]. In the hippocampus, mRNA and for both ERs have been and are well established as mediating genomic and nongenomic processes [47 ]. Nuclear and extranuclear ER #x3b2; and immunoreactivity (IR) have detected in principal cells as as in many other nuclei of within the ventral CA2/3 47 ]. Although not as prevalent as ER #x3b2; . ER has also been detected in the primarily within GABAergic [47. 49 ].

ER expression is also found to be sexually dimorphic. As one expect, many regions of the exhibit a great deal of dimorphism due in part to differences in behavior and regulation of gonadotrophic but regions such as the BNST display some sex-related in ER expression. For example, ER #x3b1; in the can be induced in somatostatin-positive neurons of but not female, rats [50 ]. ERs have been shown to be sexually in the developing rodent hippocampus, but not in [51. 52 ]. However one report ER #x3b2; mRNA in the adult but not male, rhesus macaque ganglia and hippocampus [53 ]. Importantly, a sexually dimorphic regional ER does not preclude differential to estrogens, as other effector can alter estrogen-responsive processes.

Expression of ERs can vary not only chromosomal sex, but also in to the hormonal milieu. For instance, it is accepted that ER #x3b1; is autoregulated by E 2 . primarily through degradation, [54 ] but also perhaps on a level by E 2 -bound ER #x3b2; [55 ]. The ER gene (ESR2) promoter has not been extensively characterized, but it has shown to contain E 2 -responsive cis sites for Oct-1 and Sp-1, interact with ERs via trans suggesting a molecular mechanism for E 2 autoregulation of its receptor. There is an Alu repeat sequence that may an ERE that could act as an ER-dependent [56 ]. Conversely, in vitro and in vivo investigating the effects of E 2 on ER #x3b2; have yielded inconsistent depending upon cell animal species, and age. For in the T47D human breast cell line, E 2 upregulated ER [57 ]. However, ER #x3b2; expression was by E 2 in mammary glands of lactating that coexpress ER #x3b1; [58 ]. ER was also decreased in the PVN of rats to OVX + E 2 [59 ]. Thus, it appears that E 2 may ER #x3b1; and ER #x3b2; ; however, effect is highly dependent cell type, and possibly the coexpression of other ERs.

In to sex and E 2 . aging also appears to ER expression. Overall, decreased E 2 binding has been reported in the and anterior pituitary of aged rats compared to young but the change in E 2 binding was not necessarily to a decrease in total ER expression 61 ], suggesting a shift in the ratio of ERs subcellular localization. While nuclear E 2 binding within the may decrease with age, to ER expression patterns with age contentious. In general, it appears age alone does not eliminate ER expression in the brain, but regional and E 2 availability may be important factors 63 ], and an increase in ESR promoter methylation has correlated with age in other [64. 65 ]. One study reported middle age-specific reduction in ER with E 2 treatment [66 ], yet another showed that E 2 decreased ER expression significantly in all ages (3, 11, and 20 months) [67 ]. Specific to ER #x3b1; . a by Chakraborty and colleagues determined immunoreactive cell numbers did not change following OVX and E 2 replacement. their study revealed with advanced age (24#x2013;26 compared to 3-4 and 10#x2013;12 months) the of ER #x3b1; -positive cells was or it stayed the same in different nuclei [68 ]. In the hippocampus, ER #x3b1; was after long-term estrogen (LTED, 10 weeks), regardless of E 2 following LTED, but E 2 deprivation had no on ER #x3b2; [11 ]. The same report decreased levels of ER #x3b2; in old rats (24-month females to 3-month diestrus females). In most reports suggest aging decreases ER #x3b2; but, like ER #x3b1; . effect may be highly region An age-related decrease in ER #x3b2; in the brain is underscored by a corresponding in CpG methylation of the ESR2 promoter in (9#x2013;12 months) rats [69 ]. reports describe decreases in ER protein and message in some but not in others [63. 70 ]. Taken there are a number of reports to identify the parameters that ER expression such as age, and response to E 2 ; however, with vast deviations in expression cell type there is much to be learned about of these receptors, especially in regions controlling nonreproductive

6. Alternative Splice Variants

upon the highly variable that differ in sex and age of animals as as exposure to hormone, it may be possible these studies are unknowingly changes in splice variant which could change E 2 as well as downstream gene Not only can ERs heterodimerize to regulate transcription, but there are a number of spliced variants of each that are endogenously expressed and potentially contribute to the diverse actions of E 2 . Alternative splicing of ERs inherent signaling properties of the including ligand, and DNA-binding nuclear localization, and dimerization, on where the alternative splice is encoded. A number of ER splice transcripts and other proteins been identified in demented brains, breast, and prostate, in some reports, an increase in splicing is correlated with [71 #x2013;75 ]. Also interesting, age may increase alternative splicing of gene products [76 ]. The identified ER human splice variants are at the C-terminus of the receptor (Figure ); however, we provided experimental that the C-terminus of the receptor is not for ER #x3b2; -mediated transcription, with regard to the identified splice variants [77 ]. Unlike the splice variants, rodent ER splice variants identified to have been shown to either an exon inclusion in the domain, creating (rER 2), or an exon deletion in the DNA-binding rER #x3b2; 1#x394;3 or rER #x3b2; or both rER #x3b2; 2#x394;3 and rER 2#x394;4 (Figure 1(b) ) 78. 79 ]. Exon inclusion (rER 2 variants) has been shown to a protein that binds E 2 a 35-fold decrease in affinity. In ERs with exon 3 and 4 deletions are to bind DNA, but they can mediate transcription through interactions with other factors such as AP-1, and it can E 2 as well as rER #x3b2; 1 [37. 80 ]. the transcriptional functions of rER #x3b2; 1 are altered when coexpressed other splice variants, due to a weaker interaction with proteins [81. 82 ]. Despite E 2 binding and/or lack of DNA the rodent and human splice retain a constitutive ligand-independent function, at both basic and promoters [77. 83. 84 ], suggesting these splice variants an important endogenous biological Indeed, unliganded ER #x3b2; 1 or #x3b2; 1 has been reported to a subset of genes distinct those regulated by ER #x3b2; 1 bound to E 2 [41 ]. Conversely, the human variants do not bind ligand great affinity [85 ], and they therefore only regulate the of genes that unliganded ER targets.

The downstream target of ER #x3b2; splice variants be an important consideration at the time of as ER expression profiles and alternative tend to change with age [76 ]. One report demonstrated an increase in ER 2 expression in the hippocampus of 9-month middle-aged rats following (6 days) E 2 deprivation that was decreased compared to the Sham after E 2 administration [86 ]. Importantly, E 2 no longer affected ER #x3b2; 2 in the hippocampus after LTED days). That study reported a decrease in hippocampal and increased floating behavior in a swim test, thus correlating increased ER #x3b2; 2 mood regulation and potentially Thus, the expression and functions of ER splice variants are absolutely to understand the effects of estrogen at times of sustained E 2 deprivation regard to cognition and affect. ER #x3b2; 2 expression has been in the young male rat brain [87 ], and variants have been in some brain regions 88 ], there is a general lack of on most ER #x3b2; splice especially in aged female

Some of the splice variants to date have been as dominant negative receptors, to inhibit activation of the full-length [89 ]; however, most identified do not bind ligand with the affinity and have the potential to regulate target genes. several splice variants for ER have been identified in model systems including [90 ], rat [45. 46 ], and monkey [91 ], there is a lack of comparative studies on and functionality of human ER #x3b2; especially in neuronal systems. changing expression levels of one or alternatively spliced variants a period of E 2 deprivation may drastically general receptivity and downstream of E 2.

7. Novel Protein:Protein Interactions for E 2 Nuclear Processes

Protein:protein are an essential relay in the regulation of cellular processes. Immediately translation, ERs typically associate a chaperone protein to ensure folding, protect from and assist the ER in becoming poised to ligand. Once bound to ERs can dimerize and act as transcription factors to gene regulation or associate membrane proteins to initiate a cascade. When acting as factors, ERs associate with a of coregulatory proteins that in activating or repressing E 2 -regulated Coregulatory interactions are more for ER #x3b1; than ER #x3b2; . importantly, less clear is how ER mediates ligand-independent transcription. In to the well-established ER interaction partners, novel interacting proteins not yet been characterized and could be for nuclear processes not limited to transcription.

8. HSPs and Chaperone

According to the classical two-step inactive nuclear receptors are accompanied and protected from by a number of chaperone proteins, members of the heat-shock protein family. This receptor:chaperone has been studied extensively, and the idea of a protective role for is well supported, this can also perform other For instance, HSP:ER complexes can to preactivate a hormone receptor by a conformational change in ER such it is able to bind its cognate The initial HSP complex consists of the ER, and HSP70-interacting protein (HiP), as as other accessory and scaffolding [92 ]. HSP90 is recruited to the complex, and dissociates, creating the mature complex [93 ]. HSP90 induces a change in the nuclear receptor, and the ER is from the complex, ready to and bind DNA or other transcription to regulate gene transcription. some studies suggest HSPs could have a role than originally For example, in Drosophila, HSPs are for DNA binding, and in some instances may regulate NR action [94 ]. Interestingly, and E 2 can alter HSP70 in a cell-type manner [95 #x2013;98 ]. However, data from our lab (Table 1 ) that HSP70 more associates with ER #x3b2; in female hippocampus following E 2 compared to the young ones in HSP70:ER #x3b2; association following E 2 treatment. We also no significant changes in HSP70 or ER expression, suggesting that in the HSP70:ER #x3b2; interaction age in response to E 2 change are a result of E 2 and/or activation of ER #x3b2; .

Volkswagen 412 Variant
Volkswagen 412 Variant
Volkswagen 412 Variant
Volkswagen 412 Variant
Volkswagen 412 Variant


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