scholarly journals Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome

2021 ◽  
Vol 14 (11) ◽  
pp. 1170
Author(s):  
Wenche Stensen ◽  
Ulli Rothweiler ◽  
Richard Alan Engh ◽  
Melissa R. Stasko ◽  
Ilya Bederman ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Deficits ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Chromosome 21 ◽  
The Novel ◽  
Behavioral Challenges ◽  
Early Onset Alzheimer’S Disease ◽  
Encoding Gene ◽  
Complex Genetic Disorder

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.

scholarly journals Gambaran Erupsi Gigi Permanen pada Anak Sindrom Down Usia 10-16 Tahun di Sekolah Luar Biasa Kabupaten Jember

2018 ◽  
Vol 8 (1) ◽  
pp. 8
Author(s):  
Loly Anastasya Sinaga ◽  
Dwi Kartika Apriyono ◽  
Masniari Novita
Keyword(s):  
Down Syndrome ◽  
Special Needs ◽  
Physical Characteristic ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Extra Chromosome ◽  
Descriptive Study ◽  
Chromosome 21 ◽  
Permanent Teeth ◽  
Intellectual Abilities

Background: Down Syndrome is a genetic disorder that occurs because of chromosome 21 has three chromosome (trisomy 21). The extra chromosome changes the genetic balance, physical characteristic, intellectual abilities, and physiological body function. Tooth eruption in Down Syndrome children typically delayed in both the timing and sequence of eruption up to two or three years. Objective: To observe the permanent teeth eruption in Down syndrome children at age 10-16 years old, boys and girls in Special Needs School in Jember. Materials and Methods: This research was a descriptive study with 7 subjects. Each subject was examined then calculated teeth that had emerged or functionally eruption with articualting paper. Result and Conclusion:  Both permanent teeth that is still partially erupted tooth (emerged/ EM) and had erupted perfectly (functionally eruption/ FE) delayed in eruption in Down Syndrome boys and girls at age 10-16 years old.

scholarly journals Bioinformatics Investigation and Contribution of Other Chromosomes Besides Chromosome 21 in the Risk of Down Syndrome Development

2021 ◽  
Vol 12 (1) ◽  
pp. 79-88
Author(s):  
Mona Zamanian Azodi ◽  
◽  
Mostafa Rezaei Tavirani ◽  
Majid Rezaei Tavirani ◽  
Mohammad Rostami Nejad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Gene Expression Profile ◽  
Clinical Studies ◽  
Genetic Disorder ◽  
Research Topic ◽  
Chromosome 21 ◽  
Network Centrality ◽  
Microarray Study ◽  
Molecular Studies

Introduction: Down syndrome as a genetic disorder is a popular research topic in molecular studies. One way to study Down syndrome is via bioinformatics. Methods: In this study, a gene expression profile from a microarray study was selected for more investigation. Results: The study of Down syndrome patients shows specific genes with differential expression and network centrality properties. These genes are introduced as RHOA, FGF2, FYN, and CD44, and their level of expression is high in these patients. Conclusion: This study suggests that besides chromosomes 21, there are additional contributing chromosomes to the risk of Down syndrome development. Besides, these genes could be used for clinical studies after more analysis.

scholarly journals Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

2019 ◽  
Author(s):  
Pishan Chang ◽  
Daniel Bush ◽  
Stephanie Schorge ◽  
Mark Good ◽  
Tara Canonica ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Models ◽  
Cognitive Deficits ◽  
Memory Task ◽  
Chromosome 21 ◽  
Neural Dynamics ◽  
Human Chromosome 21 ◽  
Chromosomal Disorder ◽  
Reduced Frequency ◽  
High Gamma

SummaryAltered neural dynamics in medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder, Down Syndrome (DS). Here, we demonstrate non-overlapping behavioural differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice showed slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, increased modulation of hippocampal high gamma); Dp10Yey mice showed impaired alternation performance and reduced theta modulation of hippocampal low gamma; while Dp17Yey mice were no different from wildtype mice. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.

scholarly journals Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of down syndrome-related phenotypes

2021 ◽  
Author(s):  
Eva Lana-Elola ◽  
Heather Cater ◽  
Sheona Watson-Scales ◽  
Simon Greenaway ◽  
Jennifer Müller-Winkler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Deficits ◽  
Trisomy 21 ◽  
Heart Defects ◽  
Chromosome 21 ◽  
Phenotypic Analysis ◽  
Extra Copy ◽  
Human Chromosome 21 ◽  
Complex Phenotypes ◽  
Physiological Systems

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

scholarly journals Lamivudine, a Reverse Transcriptase Inhibitor, Rescues Cognitive Deficits in a Mouse Model of Down Syndrome

2021 ◽  
Author(s):  
Maria Martinez de Lagran ◽  
Aleix Elizalde-Torrent ◽  
Roger Paredes ◽  
Bonaventura Clotet ◽  
Mara Dierssen
Keyword(s):  
Down Syndrome ◽  
Reverse Transcriptase ◽  
Cognitive Deficits ◽  
Genetic Disorder ◽  
Transcriptase Inhibitor ◽  
Wide Range ◽  
Elevated Activity ◽  
Reverse Transcriptase Inhibitor ◽  
Common Genetic Disorder ◽  
Genetic Form

Abstract An elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases. Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and a genetic form of Alzheimer’s disease. For this reason, we hypothesized that treatment with reverse transcriptase inhibitors could ameliorate DS phenotypes. In this proof of concept study, we treated trisomic (Ts65Dn) mice, a model of DS, with lamivudine, a reverse transcriptase inhibitor. We detected a significant improvement of neurobehavioral phenotypes, and a complete rescue of the hippocampal-dependent recognition memory upon treatment with lamivudine. Despite clinical studies in patients with DS are warranted, this study lays the groundwork for a novel and actionable therapeutic approach.

Down Syndrome from a Neurodevelopmental Perspective

2016 ◽  
Author(s):  
Hana D’Souza ◽  
Jamie Edgin ◽  
Annette Karmiloff-Smith
Keyword(s):  
Down Syndrome ◽  
Individual Differences ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Developmental Time ◽  
Receptive Vocabulary ◽  
Chromosome 21 ◽  
Typically Developing ◽  
Altered Expression ◽  
Wide Range

This is an advance summary of a forthcoming article in the Oxford Research Encyclopedia of Psychology. Please check back later for the full article. Down syndrome (DS; trisomy 21) is the most common genetic disorder associated with intellectual disability. It occurs in one out of every 700 to 1,000 live births. DS is caused by trisomy of human chromosome 21, which results in the altered expression of over 300 genes. This neurodevelopmental syndrome is characterized by distinctive facial dysmorphology and an uneven cognitive phenotype including relative strengths and weaknesses. Relative strengths include visual processing, receptive vocabulary, and social-emotional functioning (though performance in these domains generally falls below the level expected for typically developing individuals). Relative weaknesses include verbal working memory, expressive language, and motor ability. However, the phenotype of individuals with DS is far from homogeneous, and a wide range of individual differences is present at every level of description. On the genetic level, the trisomy can occur through different mechanisms at distinct developmental time points, and the expression of trisomy 21 may be modulated by different genes across individuals. On the level of the brain, individual differences in brain structure and/or function correlate with variation in cognition and behavior, including communication skills. Large individual differences can also be observed on the cognitive level. For example, while some toddlers with DS are nonverbal, others reach expressive vocabulary levels close to those of typically developing children. A wide range of individual differences has also been reported in other areas, including the motor domain, sleep, parent-child interaction, and medical and psychiatric comorbidities. In order to understand a neurodevelopmental syndrome such as DS, it is crucial to consider individual variations at multiple levels of description and the interactions between them over developmental time. A more complex, dynamic view that goes beyond a description of DS as a homogenous group is thus required.

scholarly journals Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Justin L. Tosh ◽  
◽  
Elena R. Rhymes ◽  
Paige Mumford ◽  
Heather T. Whittaker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Mouse Models ◽  
Early Onset ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Early Onset Alzheimer’S Disease

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

scholarly journals Cbs overdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically with Dyrk1a

2019 ◽  
Vol 28 (9) ◽  
pp. 1561-1577 ◽  
Author(s):  
Damien Marechal ◽  
Véronique Brault ◽  
Alice Leon ◽  
Dehren Martin ◽  
Patricia Lopes Pereira ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Chromosome 21 ◽  
Pharmacological Intervention ◽  
The Novel ◽  
Cystathionine Beta Synthase ◽  
Human Chromosome 21 ◽  
Dual Specificity ◽  
Intervention Point ◽  
Intellectual Deficiencies ◽  
Necessary And Sufficient

Abstract Identifying dosage-sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) shows cognitive phenotypes that need to be investigated to identify the main genetic driver. Here, we report that three copies of the cystathionine-beta-synthase gene (Cbs) in the Dp1Yah mice are necessary to observe a deficit in the novel object recognition (NOR) paradigm. Moreover, the overexpression of Cbs alone is sufficient to induce deficits in the NOR test. Accordingly, overexpressing human CBS specifically in Camk2a-expressing neurons leads to impaired objects discrimination. Altogether, this shows that Cbs overdosage is involved in DS learning and memory phenotypes. To go further, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast. Pharmacological intervention in Tg(CBS) mice with one selected compound restored memory in the NOR test. In addition, using a genetic approach, we demonstrated an epistatic interaction between Cbs and Dyrk1a, another human chromosome 21-located gene (which encodes the dual-specificity tyrosine phosphorylation-regulated kinase 1a) and an already known target for DS therapeutic intervention. Further analysis using proteomic approaches highlighted several molecular pathways, including synaptic transmission, cell projection morphogenesis and actin cytoskeleton, that are affected by DYRK1A and CBS overexpression. Overall, we demonstrated that CBS overdosage underpins the DS-related recognition memory deficit and that both CBS and DYRK1A interact to control accurate memory processes in DS. In addition, our study establishes CBS as an intervention point for treating intellectual deficiencies linked to DS.

scholarly journals Síndrome de down: facilidades, dificuldades e apoio encontrado pelos pais / Down syndrome: facilities, dificulties and support found by parents

2017 ◽  
Vol 7 (2) ◽  
pp. 23-29
Author(s):  
Mayra Cristina Martins dos Santos ◽  
Ana Camila Batista ◽  
Ivandira Anselmo Ribeiro Simões
Keyword(s):  
Down Syndrome ◽  
Mental Retardation ◽  
Exploratory Study ◽  
Social Representations ◽  
Genetic Disorder ◽  
Structured Interview ◽  
Chromosome 21 ◽  
Professional Characteristics ◽  
Qualitative Descriptive ◽  
Answering Questions

Introdução: A síndrome de Down (SD) é um distúrbio genético, devido à presença adicional de um cromossomo 21 nas células de seu portador e que causa um retardo mental de vários graus. Objetivos: Identificar quais as dificuldades e facilidades que os pais tiveram na criação de seus filhos com a SD e conhecer que tipos de apoio os pais dos portadores da SD receberam. Métodos: Pesquisa do tipo qualitativa, descritiva e exploratória. Para a análise e interpretação dos dados utilizou-se a técnica do Discurso do Sujeito Coletivo, que tem como base as Teorias das Representações Sociais. O local do estudo foi na APAE de Itajubá. A amostragem foi por conveniência; a amostra foi inicialmente constituída por 30 participantes que possuem filhos com a SD. No entanto, responderam à pergunta semiestruturada 14 participantes, os demais alegaram não ter interesse e estarem cansados em responder perguntas relacionadas ao tema; assim a amostra constou de 14 participantes. Os instrumentos utilizados na coleta de dados foram dois: um roteiro de entrevista semiestruturada e outro que contempla informações relacionadas à caracterização pessoal e profissional dos participantes do estudo. Resultados: As Ideias Centrais (IC) quanto à questão relacionada às facilidades foram: APAE, amigos, nenhuma e psicóloga. Quanto às dificuldades, foram: não teve, muitas dificuldades, não poder estudar em outra escola e saber até onde iria chegar. Já quanto ao apoio, foram as seguintes: APAE e comunidade. Conclusão: Observou-se que o desenvolvimento da pessoa portadora de SD está fortemente relacionado com a APAE, pois foi a própria APAE que os acolheu e os ajudou a conseguirem o que almejaram.Palavras-chave: Síndrome de down; Pais; EnfermagemABSTRACTIntroduction: The Down Syndrome (DS) is a genetic disorder characterized by the additional presence of the chromosome 21 in the patients´ cells and that causes a spectrum of mental retardation. Aims: To identify which difficulties and facilities parents have in raising their children with DS and know what kind of support the parents of DS patients received. Methods: It is a qualitative, descriptive, and exploratory study. For analysis and interpretation of the data it was used the Collective subject discourse technique, which is based on the Theory of Social Representations. The study site was the APAE of Itajubá. Sampling was purposeful; the sample was initially composed of 30 participants who have children with DS. However, only 14 participants answered the semi-structured questions, for the others claimed to have no interest and were tired of answering questions related to the topic; therefore the sample consisted of 14 participants. The instruments used in data collection were two: one set of semi-structured interview questions and another that included information related to the personal and professional characteristics of the participants. Results: The Central Ideas (CI) regarding the question related to the facilities were: APAE, friends, none, and psychologist. As for the difficulties, they were as following: none, many difficulties, not to study in another school and how far they would go. As for the support, they were: APAE and community. Conclusion: It was observed that the development of the DS carrier person is strongly related to APAE because it is the institution that welcomed them and helped them get what they longed for.Keywords: Down syndrome; Parents; Nursing

scholarly journals Evaluation of postural control in children and adolescents with down syndrome aged eight to twelve years old

2018 ◽  
Vol 28 (1) ◽  
pp. 50
Author(s):  
Jessica Cristina Leite ◽  
Jéssica Caroliny de Jesus Neves ◽  
Leonardo George Victorio Vitor ◽  
Dirce Shizuko Fujisawa
Keyword(s):  
Down Syndrome ◽  
Nutritional Status ◽  
Postural Control ◽  
Children And Adolescents ◽  
Center Of Pressure ◽  
Genetic Disorder ◽  
Statistical Significance ◽  
Chromosome 21 ◽  
Cross Sectional ◽  
Convenience Sample

Introduction: Down Syndrome is a genetic disorder caused by the presence of the third copy of chromosome 21 (total or partial). The syndrome occurs in approximately one out of every 700 – 1000 newborns per year. Objective:To analyze postural control (PC) of children and adolescents with Down Syndrome (DS) and to compare differences regarding age, sex, nutritional status, and physical activity (PA) levels. Methods: In this cross-sectional study, a convenience sample composed of 21 children and adolescents (9 girls) was categorized according to age: G1 (8 to 9 years old; n = 8), G2 (10 years old; n = 7), and G3 (11 to 12 years old; n = 6), Score-Z: eutrophic (n = 9) and overweight (n = 12), and PA level: practitioners (n = 7) and non-practitioners (n = 14). PC was assessed in the force platform (FP), in the standing position, with feet together during 30 seconds. The variables analyzed were the center of pressure area (COP) and the mean velocities of anteroposterior and mediolateral oscillation (VEL-AP and VEL-ML). Shapiro-Wilk test was used to test the normality of data. Kruskal-Wallis, Dunn’s, and Mann Whitney tests were performed to analyze associations with PC. Statistical significance was set at p<0.05. Results: The median COP, VEL-AP and VEL-ML were 3.55 [2.13 – 6.82] , 2.81 [2.32 – 3.16], and 2.98 [2.42 – 3.43], respectively. There were no differences in PC regarding sex, body mass index and PA level. The adolescents in G3 presented lower values of VEL-AP (G1=2,88 [2,82 – 3,21]; G2= 2,94 [2,35 – 3,39]; G3= 2,27 [2 – 2,3]) and VEL-ML (G1= 3,22 [3,14 – 3,68]; G2= 2,91 [2,52 – 3,63]; G3= 2,34 [2,1 – 2,39]). Conclusion: Sex, nutritional status, and PA level did not affect COP area and AP-VEL and ML-VEL. However, strategies were affected by age, as observed by differences in velocity, but did not affect the COP area.  

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