scholarly journals The expression profile of miR-3099 during neural development of Ts1Cje mouse model of Down syndrome

2021 ◽  
Vol 4 (1) ◽  
pp. 7-15
Author(s):  
Shahidee Zainal Abidin ◽  
Han-Chung Lee ◽  
Syahril Abdullah ◽  
Norshariza Nordin ◽  
Pike-See Cheah ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Neural Development ◽  
Progenitor Cell ◽  
Neuronal Cell ◽  
Expression Level ◽  
Wild Type ◽  
Nestin Expression ◽  
Cell Markers ◽  
Expression Levels

MicroRNA-3099 (miR-3099) plays a crucial role in regulating neuronal differentiation and development of the central nervous system (CNS). The miR-3099 is a pro-neuronal miRNA that promotes neural stem/progenitor cell (NSPC) differentiation into neuronal lineage by suppressing astrogliogenesis. Down syndrome (DS) brain exhibited increased astrogliogenesis and reduced neuronal cell density. The involvement of miR-3099 in the neurodevelopment of DS has not been investigated and potentially responsible for the neurogenic-to-gliogenic shift phenomenon observed in DS brain. To investigate the role of miR-3099 during DS brain development, neural/progenitor cell proliferation and differentiation, we profiled miR-3099 expression level in the Ts1Cje, a mouse model for DS. We analysed the Ts1Cje whole brain at embryonic day (E) 10.5, E14.5 and P1.5, proliferating neurospheres and differentiating neurospheres at 3, 9 and 15 days in vitro (DIV). Expression of miR-3099 in both the developing mouse brain and the differentiating neurosphere was not significantly different between Ts1Cje and wild type controls. In contrast, the expression level of miR-3099 was significantly higher (p<0.05) in proliferating NSPC derived from the Ts1Cje compared to wild-type. Further molecular profiling of NPSC and glial cell markers indicated that the expression of Sox2 (p<0.01) and Gfap (p<0.05) were significantly downregulated in Ts1Cje neurospheres as compared to that of wild type, respectively. While there were no significant differences in Tuj1 and Nestin expression levels between the Ts1Cje and wild type neurospheres, their expression levels were ~3-fold upregulated and ~2.6 downregulated Ts1Cje group, respectively. The findings suggest that dysregulation of miR-3099 affects NSPC lineage commitment as indicated by altered postmitotic neuronal cell markers. Further molecular characterisation and gene expression profiling of other neuronal and glial markers will help refine the analysis of gene-gene interactions underlying the neuropathologies of DS.

scholarly journals Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

2021 ◽  
Author(s):  
Anna Vazquez-Oliver ◽  
Silvia Perez-Garcia ◽  
Nieves Pizarro ◽  
Laura Molina-Porcel ◽  
Rafael de la Torre ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Side Effects ◽  
Mouse Model ◽  
Neurological Deficits ◽  
Wild Type ◽  
Male And Female ◽  
Cannabinoid Type 1 Receptor ◽  
Cognitive Improvement

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimer s disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

scholarly journals Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

2020 ◽  
Vol 21 (3) ◽  
pp. 1133 ◽  
Author(s):  
Baruh Polis ◽  
Kolluru D. Srikanth ◽  
Vyacheslav Gurevich ◽  
Naamah Bloch ◽  
Hava Gil-Henn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Adult Neurogenesis ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Cell Number ◽  
Wild Type ◽  
Newborn Neuron

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

Twisted Gastrulation (TWSG1) Is Expressed at Elevated Levels in Thalassemia and Regulates Bone Morphogenic Protein Signaling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1785-1785
Author(s):  
Toshihiko Tanno ◽  
Prashanth Porayette ◽  
Ajoy Bhupatiraju ◽  
Pamela Staker ◽  
Y. Terry Lee ◽  
...  
Keyword(s):  
Mouse Model ◽  
Quantitative Pcr ◽  
Hepatoma Cell ◽  
Bone Morphogenic Protein ◽  
Bmp Signaling ◽  
Hepatoma Cell Line ◽  
Wild Type ◽  
Expression Levels ◽  
Hepcidin Expression ◽  
Twisted Gastrulation

Abstract Iron overload and bony abnormalities cause considerable morbidity among patients with thalassemia syndromes. One possible explanation for this phenomenon is that proteins normally secreted into the marrow microenvironment during erythropoiesis are over-expressed in thalassemia patients due to expanded and ineffective erythropoiesis. We previously discovered that GDF15 is produced at very high levels in thalassemia patients and inhibits hepcidin expression. Transcriptome screens of erythroblasts were utilized here to identify twisted gastrulation (TWSG1) as a second candidate protein for further study. Quantitative PCR using the β-thalassemia murine model (Hbbth3/+ β-thalassemia intermedia mouse model, n=13; Hbbth3/th3 β-thalassemia major mouse model, n=5) revealed that splenic expression levels of Tsg (murine TWSG1) were significantly higher in thalassemia mice (Hbbth3/+, 2.2E02 ± 2.7E01 copies/ng RNA, p&lt;0.01; Hbbth3/th3, 5.3E02 ± 6.8E01 copies/ng RNA, p&lt;0.01) than among wild type mice (4.7E01 ± 2.4E01 copies/ng RNA, n=7). Bone marrow expression of Tsg was elevated (Hbbth3/+, 1.1E02 ± 3.2E01 copies/ng RNA, p=0.17; Hbbth3/th3, 1.3E02 ± 2.2E01 copies/ng RNA, p&lt;0.05) compared with wild type mice (5.3E01 ± 2.5E01 copies/ng RNA). Tsg expression levels in the murine liver were also significantly higher (Hbbth3/+, 2.8E02 ± 4.6E01 copies/ng RNA, p&lt;0.05; Hbbth3/th3, 3.9E02 ± 4.9E01 copies/ng RNA, p&lt;0.01) than in wild type mice (1.5E02 ± 4.0E01 copies/ng RNA). These results suggest that expression of Tsg is up-regulated in the murine β-thalassemia model. By comparison, murine Tsg expression was up-regulated to a greater extent than GDF15 in the thalassemia mice. In addition to murine studies, human studies of TWSG1 were performed. Quantitative PCR using cultured human CD34+ cells demonstrated the highest-level expression of TWSG1 at the early stages of erythroblast differentiation (9.3E02 ± 1.4E02 copies/ng RNA). Preliminary ELISA analyses demonstrated statistically significant elevations in TWSG1 levels in serum from thalassemia patients (n=18, 463 ± 41 ng/ml) when compared to serum from healthy volunteers (n=10, 310 ± 45 ng/ml, p&lt;0.05), but the relative increase in TWSG1 in humans was far less than previously reported for GDF15. To determine whether TWSG1 regulates hepcidin expression, assays were performed using a human hepatoma cell line (HuH-7). Unlike GDF15, TWSG1 did not directly affect hepcidin expression as measured by quantitative PCR in dosed assays (1–1,000 ng/ml TWSG1). However, TWSG1 was found to suppress hepcidin through an indirect mechanism involving bone morphogenic protein (BMP). BMPs regulate several tissue-specific processes including bone remodeling and induction of hepcidin expression in liver cells. In dosed-titrations, ≥100 ng/ml of TWSG1 resulted in a 50% reduction (p&lt;0.05) in the BMP2 augmentation of hepcidin expression. These novel data suggest that TWSG1 is expressed at elevated levels in thalassemia and has the potential to affect BMP signaling processes including the regulation of hepcidin.

scholarly journals Potassium channel regulators are differentially expressed in hippocampi of Ts65Dn and Tc1 Down syndrome mouse models

2018 ◽  
Author(s):  
Shani Stern ◽  
Rinat Keren ◽  
Yongsung Kim ◽  
Elisha Moses
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Potassium Channel ◽  
Mouse Models ◽  
Chromosome 21 ◽  
Neuronal Cultures ◽  
Rna Expression ◽  
Genetic Changes ◽  
Expression Levels ◽  
Whole Cell Patch Clamp

AbstractBackground:Down syndrome remains the main genetic cause of intellectual disability, with an incidence rate of about 1 in 700 live births. The Ts65Dn mouse strain, with an extra murine chromosome that includes genes from chromosomes 10, 16 and 17 of the mouse and the Tc1 strain with an extra human chromosome 21, are currently accepted as informative and well-studied models for Down Syndrome. Using whole cell patch clamp we recently showed changes in several types of transmembrane currents in hippocampal neuronal cultures of Ts65Dn and Tc1 embryos. The associated genetic changes responsible for these changes in physiology were yet to be studied.Methods:We used qPCR to measure RNA expression level of a few of the channel genes that we suspect are implicated in the previously reported changes of measured currents, and performed statistical analysis using Matlab procedures for the standard t-test and ANOVA and for calculating correlations between the RNA expression levels of several channel genes.Results:We present differential gene expression levels measured using qPCR of the potassium channel regulators KCNE1 and KCNE2 in both Ts65Dn and Tc1 embryos and pups compared to controls. In Tc1, the human genes KCNJ6 and KCNJ15 are expressed in addition to a statistically insignificant increase of expression in the mouse genes KCNJ6 and KCNJ15. All channel genes that we have measured with large replication, have the same up-regulation or down-regulation in both mouse models, indicating that the transcription mechanism acts similarly in these two mouse models. The large dataset furthermore allows us to observe correlations between different channel genes. We find that, despite the significant changes in expression levels, channels that are known to interact have a high and significant correlation in expression both in controls and in the Down syndrome mouse model.Conclusions:We suggest the differential expression of KCNE1 and KCNE2 as a possible cause for our previously reported changes in potassium currents. We report a KCNJ6 and KCNJ15 overexpression, which plays a role in the increased input conductance and the reduced cell excitability that we previously reported in the Tc1 mouse model. The large and significant positive (KCNQ2-KCNQ3, KCNE1-KCNE2, KCNQ3-KCNE1, KCNQ2-KCNE1, KCNQ2-KCNE2, KCNQ3-KCNE2) and negative correlations (KCNE1-KCNJ15, KCNE2-KCNJ15) that we find between channel genes indicate that these genes probably work in a cooperative or in a mutually exclusive manner.

scholarly journals Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

2019 ◽  
Author(s):  
Baruh Polis ◽  
Vyacheslav Gurevich ◽  
Naamah Bloch ◽  
Abraham O. Samson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Adult Neurogenesis ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Cell Number ◽  
Wild Type ◽  
Newborn Neuron

AbstractAdult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis.Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administer an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and apply an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy.Remarkably, we evidence a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline shows no significant effect upon the progenitor cell number and constitution. We demonstrate that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identify a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome

Blood ◽  
2010 ◽  
Vol 115 (19) ◽  
pp. 3966-3969 ◽  
Author(s):  
Ashley P. Ng ◽  
Craig D. Hyland ◽  
Donald Metcalf ◽  
Catherine L. Carmichael ◽  
Stephen J. Loughran ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Trisomy 21 ◽  
Progenitor Cell ◽  
Gene Dosage ◽  
Myeloproliferative Disorder ◽  
Chromosome 21 ◽  
Loss Of Function ◽  
Hematologic Disorders ◽  
Acute Megakaryocytic Leukemia

Abstract Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(1716)65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(1716)65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.

scholarly journals Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of CaV1 Channels

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141985681 ◽  
Author(s):  
Artur S. Miranda ◽  
Pablo Leal Cardozo ◽  
Flavia R. Silva ◽  
Jessica M. de Souza ◽  
Isabella G. Olmo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Involuntary Movement ◽  
Neuronal Cell ◽  
The Body ◽  
Glutamate Toxicity ◽  
Wild Type ◽  
Vitro Assay

Huntington’s disease (HD) is a neurodegenerative autosomal dominant disorder, characterized by symptoms of involuntary movement of the body, loss of cognitive function, psychiatric disorder, leading inevitably to death. It has been previously described that higher levels of brain expression of Cav1 channels are involved in major neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Our results demonstrate that a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD mice) at the age of 3 and 12 months exhibits significantly increased Cav1.2 protein levels in the cortex, as compared with wild-type littermates. Importantly, electrophysiological analyses confirm a significant increase in L-type Ca2+ currents and total Ca2+ current density in cortical neurons from BACHD mice. By using an in vitro assay to measure neuronal cell death, we were able to observe neuronal protection against glutamate toxicity after treatment with Cav1 blockers, in wild-type and, more importantly, in BACHD neurons. According to our data, Cav1 blockers may offer an interesting strategy for the treatment of HD. Altogether, our results show that mutant huntingtin (mHtt) expression may cause a dysregulation of Cav1.2 channels and we hypothesize that this contributes to neurodegeneration during HD.

scholarly journals A new analytical pipeline reveals metatranscriptomic changes upon high-fat diet in a Down syndrome mouse model.

2021 ◽  
Author(s):  
Ilona Ewa Grabowicz ◽  
Julia Herman-Iżycka ◽  
Marta Fructuoso ◽  
Mara Dierssen ◽  
Bartek Wilczynski
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Gut Microbiome ◽  
High Fat Diet ◽  
Functional Annotation ◽  
Gene Selection ◽  
High Fat ◽  
Contig Assembly ◽  
Expression Levels ◽  
Very High

The existing methods designated for metatranscriptomic studies are still rare and being developed. In this paper we present a new analytical pipeline combining contig assembly, gene selection and functional annotation. This pipeline allowed us to reconstruct contigs with very high unique mappability (83%) and select sequences encoding putative bacterial genes reaching also a very high (66%), unique mappability of the NGS sequencing reads. Then, we have applied our pipeline to study faecal metatranscriptome of a Down syndrome (DS) mouse model, the Ts65Dn mice, in order to identify the differentially expressed transcripts. Recent studies have implicated dysbiosis of gut microbiota in several central nervous system (CNS) disorders, including DS. Given that DS individuals have an increased prevalence of obesity, we also studied the effects of a high-fat diet (HFD) on the transcriptomic changes of mice gut microbiomes, as the complex symbiotic relationship between the gut microbiome and its host is strongly influenced by diet and nutrition. Using our new pipeline we found that compared to wild type (WT), Ts65Dn mice showed an elevated expression levels of genes involved in hypoxanthine metabolism, which contributes to oxidative stress, and a down-regulated expression of genes involved in interactions with host epithelial cells and virulence. Microbiomes of mice fed HFD showed significantly higher expression levels of genes involved in membrane lipopolysaccharides / lipids biosynthesis, and decreased expression of osmoprotection and lysine fermentation genes, among others. We also found evidence that mice microbiota is capable of expressing genes encoding for neuromodulators, which may play a role in development of compulsive overeating and obesity. Our results show a DS-specific metatranscriptome profile and show that a high-fat diet affects the metabolism of mice gut microbiome by changing activity of genes involved in lipids, sugars, proteins and amino acids metabolism and cell membranes turnover. Our new analytical pipeline combining contig assembly, gene selection and functional annotation provides new insights into the metatranscriptomic studies.

scholarly journals Interleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment

2020 ◽  
Vol 126 (3) ◽  
pp. 315-329 ◽  
Author(s):  
Yujia Yue ◽  
Chunlin Wang ◽  
Cindy Benedict ◽  
Grace Huang ◽  
May Truongcao ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Left Ventricle ◽  
Mouse Model ◽  
Endothelial Progenitor Cell ◽  
Progenitor Cell ◽  
Interleukin 10 ◽  
Wild Type ◽  
Myocardial Repair ◽  
Scar Size ◽  
Integrin Linked Kinase

Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-10) deficient-EPC–derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell–derived exosomes (TNFα inflamed mouse cardiac endothelial cell–derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB–dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size, and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC-derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes, and ILK-mediated activation of NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome–mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.

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