Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model
Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enric...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/89763 |
| _version_ | 1797257911063281664 |
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| author | Sergi Llambrich Birger Tielemans Ellen Saliën Marta Atzori Kaat Wouters Vicky Van Bulck Mark Platt Laure Vanherp Nuria Gallego Fernandez Laura Grau de la Fuente Harish Poptani Lieve Verlinden Uwe Himmelreich Anca Croitor Catia Attanasio Zsuzsanna Callaerts-Vegh Willy Gsell Neus Martínez-Abadías Greetje Vande Velde |
| author_facet | Sergi Llambrich Birger Tielemans Ellen Saliën Marta Atzori Kaat Wouters Vicky Van Bulck Mark Platt Laure Vanherp Nuria Gallego Fernandez Laura Grau de la Fuente Harish Poptani Lieve Verlinden Uwe Himmelreich Anca Croitor Catia Attanasio Zsuzsanna Callaerts-Vegh Willy Gsell Neus Martínez-Abadías Greetje Vande Velde |
| author_sort | Sergi Llambrich |
| collection | DOAJ |
| description | Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments. |
| first_indexed | 2024-04-24T22:45:09Z |
| format | Article |
| id | doaj.art-d1bf3adbb5e949bbaf5fbc9292d9e0ff |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T22:45:09Z |
| publishDate | 2024-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d1bf3adbb5e949bbaf5fbc9292d9e0ff2024-03-18T14:02:52ZengeLife Sciences Publications LtdeLife2050-084X2024-03-011210.7554/eLife.89763Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse modelSergi Llambrich0https://orcid.org/0000-0001-9980-0208Birger Tielemans1Ellen Saliën2Marta Atzori3Kaat Wouters4Vicky Van Bulck5https://orcid.org/0000-0002-9355-0567Mark Platt6Laure Vanherp7Nuria Gallego Fernandez8Laura Grau de la Fuente9Harish Poptani10Lieve Verlinden11Uwe Himmelreich12https://orcid.org/0000-0002-2060-8895Anca Croitor13Catia Attanasio14https://orcid.org/0000-0001-8077-5719Zsuzsanna Callaerts-Vegh15https://orcid.org/0000-0001-9091-2078Willy Gsell16https://orcid.org/0000-0001-7334-6107Neus Martínez-Abadías17https://orcid.org/0000-0003-3061-2123Greetje Vande Velde18https://orcid.org/0000-0002-5633-3993Biomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumDepartment of Human Genetics, KU Leuven, Leuven, BelgiumLaboratory of Biological Psychology, KU Leuven, Leuven, BelgiumLaboratory of Biological Psychology, KU Leuven, Leuven, BelgiumCentre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United KingdomBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumDepartament de Biologia Evolutiva, Ecologia i Ciències Ambientals (BEECA), Facultat de Biologia, Universitat de Barcelona, Barcelona, SpainDepartament de Biologia Evolutiva, Ecologia i Ciències Ambientals (BEECA), Facultat de Biologia, Universitat de Barcelona, Barcelona, SpainCentre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United KingdomClinical and Experimental Endocrinology, KU Leuven, Leuven, BelgiumBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumDepartment of Human Genetics, KU Leuven, Leuven, BelgiumLaboratory of Biological Psychology, KU Leuven, Leuven, BelgiumBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumDepartament de Biologia Evolutiva, Ecologia i Ciències Ambientals (BEECA), Facultat de Biologia, Universitat de Barcelona, Barcelona, SpainBiomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, BelgiumDown syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.https://elifesciences.org/articles/89763Down syndromeintegrated developmentcognitionBoneRNABrain |
| spellingShingle | Sergi Llambrich Birger Tielemans Ellen Saliën Marta Atzori Kaat Wouters Vicky Van Bulck Mark Platt Laure Vanherp Nuria Gallego Fernandez Laura Grau de la Fuente Harish Poptani Lieve Verlinden Uwe Himmelreich Anca Croitor Catia Attanasio Zsuzsanna Callaerts-Vegh Willy Gsell Neus Martínez-Abadías Greetje Vande Velde Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model eLife Down syndrome integrated development cognition Bone RNA Brain |
| title | Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model |
| title_full | Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model |
| title_fullStr | Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model |
| title_full_unstemmed | Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model |
| title_short | Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model |
| title_sort | pleiotropic effects of trisomy and pharmacologic modulation on structural functional molecular and genetic systems in a down syndrome mouse model |
| topic | Down syndrome integrated development cognition Bone RNA Brain |
| url | https://elifesciences.org/articles/89763 |
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