Estrogen Signaling and the Aging Brain ContextDependent Considerations… — Volkswagen 412 Variant

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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, …, 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 …, 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, …, 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, … 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 … 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 …-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 … in the developing rodent hippocampus, but not in [51. 52 ]. However one report ER #x3b2; mRNA in the … but not male, rhesus macaque ganglia and hippocampus [53 ]. Importantly, a … 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 …, 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 … and E 2 . aging also to influence ER expression. Overall, nuclear E 2 binding has been in the hypothalamus and anterior pituitary of female rats compared to ones, but the change in E 2 binding was not attributed to a decrease in total ER [60. 61 ], suggesting a shift in the of ERs and/or subcellular localization. overall nuclear E 2 binding the hypothalamus may decrease with changes to ER expression patterns age remain contentious. In general, it that age alone does not ER #x3b1; expression in the brain, but specificity and E 2 availability may be important [62. 63 ], and an increase in ESR promoter has been correlated with age in systems [64. 65 ]. One study varied middle age-specific in hypothalamic ER with E 2 treatment [66 ], yet study showed that E 2 hypothalamic ER expression significantly in all tested (3, 11, and 20 months) [67 ]. Specific to ER . a work by Chakraborty and colleagues that immunoreactive cell did not always change following OVX and E 2 Rather, their study that with advanced age months compared to 3-4 and 10#x2013;12 the number of ER #x3b1; -positive was increased or it stayed the same in hypothalamic nuclei [68 ]. In the hippocampus, ER was decreased after long-term deprivation (LTED, 10 weeks), of E 2 replacement following LTED, but E 2 had no effect on ER #x3b2; [11 ]. The same demonstrated decreased levels of ER in very old rats (24-month compared to 3-month diestrus In general, most reports that aging decreases ER expression, but, like ER . this effect may be highly specific. An age-related decrease in ER expression in the brain is underscored by a increase in CpG methylation of the ESR2 in middle-aged (9#x2013;12 months) [69 ]. Other reports describe in ER #x3b2; protein and message in areas but not in others [63. 70 ]. together, there are a number of attempting to identify the parameters control ER expression such as …, and response to E 2 ; however, such vast deviations in with cell type is still much to be learned expression of these receptors, in brain regions controlling behaviors.

6. Alternative Splice Variants

upon the highly variable that differ in … and age of as well as exposure to hormone, it may be that these studies are detecting changes in splice expression, which could E 2 responsiveness as well as downstream regulation. Not only can ERs heterodimerize to gene transcription, but there are a of alternatively spliced variants of receptor that are endogenously and that potentially contribute to the tissue-specific actions of E 2 . Alternative of ERs alters inherent signaling of the receptor including ligand, and affinities, nuclear localization, and depending on where the alternative site is encoded. A number of ER variant transcripts and other have been identified in human brains, breast, and and, in some reports, an in alternative splicing is correlated pathology [71 #x2013;75 ]. Also age alone may increase alternative of some gene products [76 ]. The ER #x3b2; human splice are truncated at the C-terminus of the receptor 1(a) ); however, we provided evidence that the C-terminus of the is not required for ER #x3b2; -mediated especially with regard to the human splice variants [77 ]. the human splice variants, ER #x3b2; splice variants to date have been to have either an exon in the ligand-binding domain, creating #x3b2; 2), or an exon deletion in the domain rER #x3b2; 1#x394;3 or rER 1#x394;4 or both rER #x3b2; and rER #x3b2; 2#x394;4 (Figure ) [37. 78. 79 ]. Exon inclusion #x3b2; 2 variants) has been to produce a protein that E 2 with a 35-fold decrease in In contrast, ERs with exon 3 and 4 are unable to bind DNA, but can still mediate transcription protein:protein interactions with transcription factors such as and it can bind E 2 as well as rER #x3b2; 1 80 ]. Importantly, the transcriptional functions of rER 1 are significantly altered when with other splice likely due to a weaker interaction coactivator proteins [81. 82 ]. lower E 2 binding and/or of DNA binding, the rodent and human variants retain a constitutive transcriptional function, at both and complex promoters [77. 83. 84 ], that these splice have an important endogenous function. Indeed, unliganded ER 1 or apo-ER #x3b2; 1 has been to regulate a subset of genes from those regulated by ER 1 when bound to E 2 [41 ]. Conversely, the splice variants do not bind with great affinity [85 ], and might therefore only the class of genes that ER #x3b2; targets.

The downstream genes of ER #x3b2; splice might be an important consideration at the of menopause, as ER expression profiles and splicing tend to change age [76 ]. One recent report demonstrated an in ER #x3b2; 2 expression in the hippocampus of old, middle-aged rats short-term (6 days) E 2 deprivation was significantly decreased compared to the group after E 2 administration [86 ]. E 2 replacement no longer affected ER 2 expression in the hippocampus after (180 days). That also reported a decrease in neurogenesis and increased floating in a forced swim test, functionally correlating increased ER 2 with mood regulation and cognition. Thus, the expression and of ER #x3b2; splice variants are critical to understand the effects of particularly at times of sustained E 2 with regard to cognition and While ER #x3b2; 2 expression has assessed in the young male rat [87 ], and other variants have described in some brain [80. 88 ], there is a general of data on most ER #x3b2; variants, especially in aged brains.

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 … 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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