Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation DOI Creative Commons
Beatrice Uguagliati, Mariagrazia Grilli

Cells, Journal Year: 2024, Volume and Issue: 13(24), P. 2037 - 2037

Published: Dec. 10, 2024

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In DS brain, since prenatal life stages, number astrocytes disproportional compared healthy brain. This increase due a shift from neuron astrocyte differentiation during brain development. Astrocytes are involved in numerous functions development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, supporting maintenance integration functional neural circuits. The enhanced individuals leads detrimental consequences for review summarizes mechanisms underlying astrocytic dysfunction DS, particularly dysregulation key signaling pathways, which promote astrogliogenesis at expense neurogenesis. It further examines implications on dendritic branching, spinogenesis synaptogenesis, impact abnormal excitability inhibitory/excitatory balance. Identifying deregulated pathways early development may help identifying new therapeutic targets, with ultimate aim ameliorating cognitive disability affects DS.

Language: Английский

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease DOI Creative Commons
Mitchell Martà-Ariza, Dominique Leitner, Evgeny Kanshin

et al.

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: Jan. 18, 2025

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar early-onset (EOAD) late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 4.07 (82.1 6.37 controls (66.4 13.04). identified differentially abundant proteins when comparing plaques neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in 132), 192), 128), 43 plaque-associated shared across all groups. Positive correlations were observed between (R2 .77), .73), .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p 1.29 × 10−5) for immune system regulation 4.33 lysosome organization 0.029) LOAD. Protein networks revealed a protein signature involving metabolism, response, functions. In vs. control tissue, we 263, 269, 301 proteins, 65 altered cohorts. Non-plaque showed modest .59) .33) compared correlation .79). GOBP term groups was chromatin remodeling 0.001), additional terms including extracellular matrix, protein–DNA complexes expression Our study reveals key functional characteristics amyloid LOAD, highlighting pathways endo/lysosomal functions responses. The distinct alterations ECM structure, underscoring unique differences subtypes. findings enhance our understanding pathogenesis identify potential biomarkers therapeutic targets.

Language: Английский

Citations

2
Using Zebrafish to Study the Mechanisms That Underlie Down Syndrome DOI
Anna J. Moyer, Summer B. Thyme

Published: Jan. 1, 2025

Language: Английский

Citations

0
Human Models of Down Syndrome DOI

Megan Jandy,

Hao Hu, Yan Liu

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells DOI Creative Commons
Ryotaro Hashizume, Sachiko Wakita, Hirofumi Sawada

et al.

PNAS Nexus, Journal Year: 2025, Volume and Issue: 4(2)

Published: Feb. 1, 2025

Abstract Human trisomy 21, responsible for Down syndrome, is the most prevalent genetic cause of cognitive impairment and remains a key focus prenatal preimplantation diagnosis. However, research directed toward eliminating supernumerary chromosomes from trisomic cells limited. The present study demonstrates that allele-specific multiple chromosome cleavage by clustered regularly interspaced palindromic repeats Cas9 can achieve rescue target human 21 induced pluripotent stem fibroblasts. Unlike previously reported allele-nonspecific strategies, we have developed comprehensive (AS) sequence extraction method efficiently removes chromosome. temporary knockdown DNA damage response genes increases loss rate, while chromosomal reversibly restores gene signatures ameliorates cellular phenotypes. Additionally, this strategy proves effective in differentiated, nondividing cells. We anticipate an AS approach will lay groundwork more sophisticated medical interventions targeting 21.

Language: Английский

Citations

0
Consequences of trisomy 21 for brain development in Down syndrome DOI
Matthew L. Russo, André M. M. Sousa, Anita Bhattacharyya

et al.

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(11), P. 740 - 755

Published: Oct. 8, 2024

Language: Английский

Citations

2
Brain volumes, cognitive, and adaptive skills in school-age children with Down syndrome DOI Creative Commons
Rebecca Grzadzinski,

Kattia Mata,

Ami S. Bhatt

et al.

Journal of Neurodevelopmental Disorders, Journal Year: 2024, Volume and Issue: 16(1)

Published: Dec. 19, 2024

Abstract Background Down syndrome (DS) is the most common congenital neurodevelopmental disorder, present in about 1 every 700 live births. Despite its prevalence, literature exploring neurobiology underlying DS and how this related to behavior limited. This study fills gap by examining cortical volumes behavioral correlates school-age children with DS. Methods School-age (mean = 9.7 years ± 1.1) underwent comprehensive assessments, including cognitive adaptive as well an MRI scan without use of sedation. Children ( n 35) were compared available samples typically developing (TD; 80) ASD 29). ANOVAs conducted compare groups on assessments. ANCOVAs (covarying for age, sex, total cerebral volume; TCV) brain between groups. Correlations metrics cerebellar (separately gray (GM) white matter (WM)) separately group. Results As expected, had significantly lower skills TD children. Daily Living comparable DS, both scored than exhibited a smaller TCV Additionally, when controlling TCV, GM tissue volumes. Cerebellum correlated behaviors group only. Conclusions exhibiting volume overall ASD, their deficits Socialization are comparable. Differences lobar (e.g., Right Frontal GM/WM, Left WM, Temporal WM) observed above beyond differences volume. The correlation cerebellum provides novel area explore future research.

Language: Английский

Citations

1
Comparison of the Amyloid Plaque Proteome in Down Syndrome, Early-Onset Alzheimer’s Disease and Late-Onset Alzheimer’s Disease DOI
Mitchell Martà-Ariza, Dominique Leitner, Evgeny Kanshin

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 15, 2024

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD), attributable to

Language: Английский

Citations

0
Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells DOI Creative Commons
Sarah E. Lee, Laura L. Baxter, Manuel Durán

et al.

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 13, 2024

Abstract Trisomy of human chromosome 21 (T21) gives rise to Down syndrome (DS), the most frequent live-born autosomal aneuploidy. T21 triggers genome-wide transcriptomic alterations that result in multiple atypical phenotypes with highly variable penetrance and expressivity individuals DS. Many these phenotypes, including neurodevelopment, emerge prenatally. To enable vitro analyses cellular molecular mechanisms leading neurological associated T21, we created characterized a panel genomically diverse euploid induced pluripotent stem cells (iPSCs). We subsequently differentiated iPSCs generate neural progenitor (NPCs). Alongside characterizing genotype effects from found NPCs showed inter-individual variability growth rates, oxidative stress, senescence characteristics, gene protein expression. Pathway enrichment identified vesicular transport, DNA repair, response stress pathways. These results demonstrate T21-associated at level suggest cell lines DS should not solely be analyzed as homogenous population. Examining large cohorts genetically samples may more fully reveal aneuploidy on phenotypic characteristics types. A (iPSCs) were into reduced growth, increased This suggests studies

Language: Английский

Citations

0
Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation DOI Creative Commons
Beatrice Uguagliati, Mariagrazia Grilli

Cells, Journal Year: 2024, Volume and Issue: 13(24), P. 2037 - 2037

Published: Dec. 10, 2024

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In DS brain, since prenatal life stages, number astrocytes disproportional compared healthy brain. This increase due a shift from neuron astrocyte differentiation during brain development. Astrocytes are involved in numerous functions development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, supporting maintenance integration functional neural circuits. The enhanced individuals leads detrimental consequences for review summarizes mechanisms underlying astrocytic dysfunction DS, particularly dysregulation key signaling pathways, which promote astrogliogenesis at expense neurogenesis. It further examines implications on dendritic branching, spinogenesis synaptogenesis, impact abnormal excitability inhibitory/excitatory balance. Identifying deregulated pathways early development may help identifying new therapeutic targets, with ultimate aim ameliorating cognitive disability affects DS.

Language: Английский

Citations

0