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Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer's disease (AD). Activation of estrogen receptor beta (ERß) can be clinically relevant since it avoids the negative systemic effects of ERα activation. However, very few studies have explored ERß-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ERß in mediating sex-specific protection against AD pathology in the clinically relevant App NL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female App NL-G-F mice with the selective ERß agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ERß-knockout mice were used to assess ERß's effect on microglial activation and phagocytosis. We find that ERß activation protects against amyloid pathology and cognitive decline in male and female App NL-G-F mice. Ovariectomy increased soluble amyloid beta (Aß) in cortex and insoluble Aß in hippocampus, but had otherwise limited effects on pathology. We further identify that ERß does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ERß protects against AD pathology differently in males and females, warranting reassessment of ERß in combating AD.
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OBJECTIVE: To study the role of estrogen receptor beta in follicle development and maturation and in the response to gonadotropin stimulation aiming at superovulation DESIGN: Experimental study and transcriptomic analysis. ANIMALS: Healthy wild-type and estrogen receptor beta (ERß) knockout female mice undergoing superovulation at 4-weeks, 7-weeks, and 6-months of age. MAIN OUTCOMES: Oocyte yield after superovulation, transcriptomic profiling of cumulus-granulosa cell complexes and oocytes, and immunohistochemical analyses. RESULTS: Superovulation of ERß knockout (Esr2-KO) mice resulted in reduced oocyte yield at 6-months of age compared to wild-type (WT) mice, but younger mice had similar yields. RNA-seq analysis of cumulus cells from superovulated WT and Esr2-KO mice identified genes and pathways associated with among others adhesion, proliferation, Wnt-signaling, and placed ERß in bipotential granulosa cell cluster. Loss of ERß increased expression of the other estrogen receptors Esr1 and Gper1. CONCLUSION: Our results show that ERß has an important role in regulating ovulation in response to exogenous gonadotropins in 6-month-old mice, but not in younger mice. Our transcriptomic and immunohistochemical observations suggest a dysregulation of the granulosa cell communication and lack of tight coordination between granulosa cell replication and antrum expansion. A significant upregulation of other estrogen receptors may support a compensatory mechanism sustaining fertility during younger age in Esr2-KO mice.
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The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.
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Enfermedad de Alzheimer , Trastornos de la Memoria , Masculino , Femenino , Humanos , Animales , Ratones , Anciano , Colesterol 24-Hidroxilasa , Trastornos de la Memoria/etiología , Colesterol , Cognición , Enfermedad de Alzheimer/genética , EstrógenosRESUMEN
Liver X receptors (LXRα and LXRß) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXRαß-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXRα and LXRß are expressed in the colonic epithelium and that in aging LXRαß-/- mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor ß (ERß) levels. The cytoplasmic compartment of the surface epithelial cells was markedly reduced and there was a massive invasion of macrophages in the lamina propria. The expression and localization of ß-catenin, α-catenin, and E-cadherin were not changed, but the shrinkage of the cytoplasm led to an appearance of an increase in staining. In the colonic epithelium there was a reduction in the expression of plectin, a hemidesmosome protein whose loss in mice leads to spontaneous colitis, ELOVL1, a fatty acid elongase protein coding gene whose overexpression is found in colorectal cancer, and non-neuronal choline acetyltransferase (ChAT) involved in the regulation of epithelial cell adhesion. We conclude that in aging LXRαß-/- mice, the phenotype in the colon is due to loss of ERß expression.
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Colitis , Receptor beta de Estrógeno , Ratones , Animales , Receptor beta de Estrógeno/metabolismo , Ratones Noqueados , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Colon/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Mucosa Intestinal/metabolismo , Sulfato de Dextran/toxicidad , Ratones Endogámicos C57BLRESUMEN
Granulosa cell tumors (GCTs) are rare ovarian tumors comprising an adult and a juvenile subtype. They have a generally good prognosis, but the survival rate drastically declines in patients with late-stage or recurring tumors. Due to the rarity of GCTs, the tumor type is largely understudied and lacks a specific treatment strategy. Estrogen receptor beta (ERß/ESR2) has been found to be highly expressed in GCTs, which could be of therapeutic importance since it can be targeted with small molecules. However, its role in GCTs is not known. In this review, we summarize the current knowledge about the action of ERß in the ovary and discuss its prospective role in GCTs.
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Tumor de Células de la Granulosa , Neoplasias Ováricas , Femenino , Humanos , Receptor beta de Estrógeno/genética , Tumor de Células de la Granulosa/metabolismo , Recurrencia Local de Neoplasia , Neoplasias Ováricas/metabolismoRESUMEN
Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients.
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Melanoma , Monocitos , Ratones , Animales , Monocitos/metabolismo , Diferenciación Celular , Colesterol/metabolismo , Presentación de Antígeno , Células Dendríticas/metabolismo , Microambiente TumoralRESUMEN
Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by subsequent excretion of the detoxified products. Degeneration and loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal neurons generally involves oxidative stress, neuroinflammation, alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction, and endoplasmic reticulum stress. However, it is still unclear what triggers these neurodegenerative processes. It has been reported that aminochrome may elicit all of these mechanisms and, interestingly, aminochrome is formed inside neuromelanin-containing dopaminergic neurons during neuromelanin synthesis. Aminochrome is a neurotoxic ortho-quinone formed in neuromelanin synthesis. However, it seems paradoxical that the neurotoxin aminochrome is generated during neuromelanin synthesis, even though healthy seniors have these neurons intact when they die. The explanation of this paradox is the existence of protective tools against aminochrome neurotoxicity composed of the enzymes DT-diaphorase, expressed in these neurons, and glutathione transferase M2-2, expressed in astrocytes. Recently, it has been reported that dopaminergic neurons can be protected by glutathione transferase M2-2 from astrocytes, which secrete exosomes containing the protective enzyme.
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Astrocytes protect neurons by modulating neuronal function and survival. Astrocytes support neurons in several ways. They provide energy through the astrocyte-neuron lactate shuttle, protect neurons from excitotoxicity, and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support, as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine. A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine, such as aminochrome and other o-quinones, were generated under neuromelanin synthesis by oxidizing dopamine catechol structure. Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity. The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.
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Sex hormones are known to interact with the immune system on multiple levels but information on the types of sex hormone receptors (SHR) and their expression levels in immune cells is scarce. Estrogen, testosterone and progesterone are all considered to interact with the immune system through their respective cell receptors (ERα and ERß including the splice variant ERß2, AR and PGR). In this study expression levels of SHR genes in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4+ and CD8+ T-cells, CD56+ NK-cells, CD14+ monocytes and CD19+ B-cells) were analyzed using standard manual qPCR or a qPCR array (TLDA). Nine healthy individuals including men (n = 2), premenopausal (Pre-MP, n = 5) and postmenopausal (post-MP, n = 2) women were sampled for PBMCs which were separated to cell subsets using FACS. Ten Pre-MP women were longitudinally sampled for total PBMCs at different phases of the menstrual cycle. We found that ERα was most abundant and, unexpectedly, that ERß2 was the dominant ERß variant in several FACS sorted cell subsets. In total PBMCs, SHR (ERα, ERß1, ERß2, and AR) expression did not fluctuate according to the phase of the menstrual cycle and PGR was not expressed. However, several immune response genes (GATA3, IFNG, IL1B, LTA, NFKB1, PDCD1, STAT3, STAT5A, TBX21, TGFB1, TNFA) were more expressed during the ovulatory and mid-luteal phases. Sex hormone levels did not correlate significantly with gene expression of SHR or immune response genes, but sex hormone-binding globulin (SHBG), a steroid hormone transporting protein, was positively correlated to expression of ERß1 gene. This study provides new insights in the distribution of ERs in immune cells. Furthermore, expression patterns of several immune response genes differ significantly between phases of the menstrual cycle, supporting a role for sex hormones in the immune response.
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Inmunidad/genética , Leucocitos Mononucleares/metabolismo , Ciclo Menstrual/genética , Receptores de Estrógenos/genética , Adulto , Anciano , Estudios de Cohortes , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Ciclo Menstrual/metabolismo , Ciclo Menstrual/fisiología , Persona de Mediana Edad , Posmenopausia/genética , Posmenopausia/metabolismo , Premenopausia/genética , Premenopausia/metabolismo , Receptores de Estrógenos/metabolismo , Factores de TiempoRESUMEN
The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERß) signaling, as well as in terms of the sex differences observed in Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.
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Enfermedad de Alzheimer , Receptores de Estrógenos , Envejecimiento , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Receptores de Estrógenos/metabolismoRESUMEN
Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor ß (LXRß) is expressed in astrocytes, and LXRß global knockout mice shows impaired synaptic formation. In order to define the role of LXRß in astrocytes, we used a conditional Cre-loxP system to specifically remove LXRß from astrocytes. We found that this deletion caused anxiety-like but not depressive-like behaviors in adult male mice. This behavioral phenotype could be completely reproduced by selective deletion of LXRß in astrocytes in the medial prefrontal cortex (mPFC). Pyramidal neurons in layer V of mPFC are involved in mood behaviors. We found that there was an increased spontaneous excitatory synaptic transmission in layer V pyramidal neurons of the mPFC of these mice. This was concurrent with increased dendritic complexity, despite normal appearance and number of dendritic spines. In addition, gene ontology analysis of RNA sequencing revealed that deletion of astrocytic LXRß led to the enrichment of the process of synaptic transmission in mPFC. Finally, we also confirmed that renormalized excitatory synaptic transmission in layer V pyramidal neurons alleviated the anxiety in mice with astrocytic LXRß deletion in mPFC. Together, our findings reveal that astrocytic LXRß in mPFC is critical in the regulation of synaptic transmission, and this provides a potential new target for treatment of anxiety-like behavior.
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Astrocitos , Corteza Prefrontal , Animales , Ansiedad/genética , Astrocitos/fisiología , Receptores X del Hígado/genética , Masculino , Ratones , Ratones Noqueados , Transmisión Sináptica/fisiologíaRESUMEN
[This corrects the article DOI: 10.1016/j.heliyon.2020.e05535.].
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The female sex hormone estradiol (E2, 17ß-estradiol) has important functions in the developing brain. In addition to regulating sexual differentiation of the brain, E2 participates in the development of brain areas involved in functions unrelated to reproduction, such as cognition. E2 signals mainly thorough two estrogen receptors; estrogen receptor alpha (ERα) and beta (ERß). While ERα has distinct functions for sexual imprinting of the developing brain, ERß is considered to participate in the development of brain areas related to cognitive function. In this chapter we will focus on ERß's role during neural development. We will discuss the contributions of sex chromosomal and sex hormonal effects in this process and place it in relation to recent data on ERß obtained from stem cell models. Finally, we will discuss the lessons learned from mouse and stem cell models in understanding ERß's role in neural development and how new stem cell models, by addressing the human relevance, may help to advance our progress in this field.
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Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Animales , Estradiol , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Femenino , Ratones , Receptores de EstrógenosRESUMEN
The enzyme glutathione transferase M2-2, expressed in human astrocytes, increases its expression in the presence of aminochrome and catalyzes the conjugation of aminochrome, preventing its toxic effects. Secretion of the enzyme glutathione transferase M2-2 from U373MG cells, used as a cellular model for astrocytes, has been reported, and the enzyme is taken up by neuroblastoma SYSH-S7 cells and provide protection against aminochrome. The present study provides evidence that glutathione transferase M2-2 is released in exosomes from U373MG cells, thereby providing a means for intercellular transport of the enzyme. With particular relevance to Parkinson disease and other degenerative conditions, we propose a new mechanism by which astrocytes may protect dopaminergic neurons against the endogenous neurotoxin aminochrome.
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Astrocitos/metabolismo , Exosomas/metabolismo , Glutatión Transferasa/metabolismo , Transporte de Proteínas , Línea Celular Tumoral , Neuronas Dopaminérgicas/metabolismo , HumanosRESUMEN
Hematopoietic stem cell- (HSC) and induced pluripotent stem (iPS) cell-derived natural killer (NK) cells containing engineered functions, such as chimeric antigen receptors (CAR), offer great promise for the treatment of seemingly incurable oncological malignancies. Today, some of the main challenges of CAR cell-based therapeutics are the long manufacturing time and safety of the cell sources used. Additional challenges include avoiding graft vs host disease (GVHD) and cytokine release syndrome (CRS). Here, we show compelling evidence for the use of NK cell therapeutics as a reliable off-the-shelf option, as they address key issues. Furthermore, we highlight how iPS cells and directed differentiation toward HSC and NK cells address industrial scalability and safety.
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Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Células Madre Pluripotentes Inducidas , Células Asesinas Naturales , Receptores Quiméricos de Antígenos , Células Madre Hematopoyéticas/citología , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Asesinas Naturales/citologíaRESUMEN
KISCOi001-A is a healthy feeder-free and fully characterized human induced pluripotent stem (iPS) cell line cultured under xeno-free and defined conditions. The cell line is generated from normal human foreskin fibroblasts with non-integrating episomal plasmid vectors encoding OCT4, SOX2, KLF4, NANOG, LIN28, nontransforming L-MYC and dominant negative p53. The generated iPS cells are transgene-free and their pluripotency is confirmed by the expression of stem cell markers and capacity to differentiate into the cells of ectoderm, endoderm and mesoderm while their identity and karyotype stability is confirmed with Genomic assays.
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Células Madre Pluripotentes Inducidas , Diferenciación Celular , Línea Celular , Fibroblastos , Prepucio , Humanos , Factor 4 Similar a Kruppel , MasculinoRESUMEN
BACKGROUND: Male estrogen receptor beta (ERß) knockout (BERKO) mice display anxiety and aggression linked to, among others, altered serotonergic signaling in the basolateral amygdala and dorsal raphe, impaired cortical radial glia migration, and reduced GABAergic signaling. The effects on primary motor cortex (M1 cortex) and locomotor activity as a consequence of ERß loss have not been investigated. OBJECTIVE: The aim of this study was to determine whether locomotor activity is altered as a consequence of the changes in the M1 cortex. METHODS: The locomotor activity of male wild-type (WT) and BERKO mice was evaluated using the open-field and rotarod tests. Molecular changes in the M1 cortex were analyzed by RNA sequencing, electron microscopy, electrophysiology, and immunohistological techniques. In addition, we established oligodendrocyte (OL) cultures from WT and BERKO mouse embryonic stem cells to evaluate OL function. RESULTS: Locomotor profiling revealed that BERKO mice were more active than WT mice but had impaired motor coordination. Analysis of the M1 cortex pointed out differences in synapse function and myelination. There was a reduction in GABAergic signaling resulting in imbalanced excitatory and inhibitory neurotransmission as well as a defective OL differentiation accompanied by myelin defects. The effects of ERß loss on OL differentiation were confirmed in vitro. CONCLUSION: ERß is an important regulator of GABAergic interneurons and OL differentiation, which impacts on adult M1 cortex function and may be linked to increased locomotor activity and decreased motor coordination in BERKO mice.
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Receptor beta de Estrógeno/genética , Locomoción/genética , Corteza Motora/fisiopatología , Vaina de Mielina/fisiología , Desempeño Psicomotor , Transmisión Sináptica , Animales , Expresión Génica , Masculino , Ratones , Ratones Noqueados , Corteza Motora/metabolismo , Oligodendroglía/patologíaRESUMEN
Men and women respond differently to infectious diseases. Women show less morbidity and mortality, partially due to the differences in sex hormone levels which can influence the immune response. Torque teno virus (TTV) is non-pathogenic and ubiquitously present in serum from a large proportion (up to 90%) of adult humans with virus levels correlating with the status of the host immune response. The source of TTV replication is unknown, but T-lymphocytes have been proposed. In this study we investigated the presence and levels of TTV in peripheral blood mononuclear cells (PBMCs) in premenopausal (pre-MP) women, post-menopausal (post-MP) women, and men, and determined their serum sex hormone levels. Of the examined subjects (n = 27), we found presence of TTV in PMBC from 17.6% pre-MP (n = 17), 25.0% post-MP (n = 4) and 50.0% men (n = 6). The levels of TTV/µg DNA were lower among TTV-positive men and post-MP women compared to pre-MP women. All the positive pre-MP women were either anovulatory, hypothyroid, or both. In addition, the TTV-positive pre-MP women had significantly lower progesterone levels compared to TTV-negative pre-MP women. Although our study was performed on a limited number of subjects, the data suggests that TTV in PBMC is associated with an anovulatory menstrual cycle with low progesterone levels, and possibly with male sex.
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Estrogen receptor beta (ERß), encoded by the Esr2 gene, is one of two nuclear receptors that mediate the functions of the steroid hormone estradiol. The binding of estradiol to the receptor results in enhanced transcription of many genes that have estrogen response elements in promoter or enhancer regions. Several genetically modified mouse lines with mutations or deletions of exons in the Esr2 gene have been developed and results from analysis of these are not completely consistent, especially regarding ERß's role in fertility. To address these controversies, we have used the CRISPR/Cas9 genome editing system to make a deletion of the entire Esr2 gene in the mouse genome and determined the effect of this mutation on fertility. We show that female Esr2 deleted mice, Esr2ΔE1-10, are subfertile at young age, with fewer litters and smaller litter size, and that they become infertile/have severely reduced fertility at around six months of age, while the male Esr2ΔE1-10 mice are fertile. Ovaries from Esr2ΔE1-10 mice are smaller than those from wild-type littermates and the morphology of the ovary displays very few corpora lutea, indicating a defect in ovulation. We also show that the estradiol levels are reduced at diestrus, the phase in the estrous cycle when levels are expected to start to increase before ovulation. Our results verify that ERß has an important function in female reproduction, likely as a regulator of serum estradiol levels, and that its loss does not affect male reproductive function.
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Receptor beta de Estrógeno/genética , Fertilidad , Animales , Sistemas CRISPR-Cas , Exones , Femenino , Eliminación de Gen , Masculino , Ratones , Ovario/fisiología , OvulaciónRESUMEN
Despite the obvious sex differences in many of the most common neuropsychiatric and neurodegenerative disorders, males and females are still often treated the same from a clinical perspective. Why is that? The simple answer is that there is still too little known about this very complex matter. Sex hormone signaling, genetic sex, sex-biased comorbidities, and social gender perceptions all interact, making discrimination between the impacts of each of these factors hard to evaluate. Adding to the complexity is that important species differences must be taken into account when interpreting data from animal models. Clearly, to overcome this, larger efforts are needed that incorporate epidemiological, experimental, and clinical data to provide a solid scientific base for more personalized and informed clinical decisions that will benefit both men and women suffering from neurological disorders.