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Cited by 242Down syndrome and intellectual disability researchAlzheimer's disease research and treatmentsGenetics and Neurodevelopmental Disorders

Gene expression profiling in the adult Down syndrome brain

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Lockstone, H.E., Harris, L.W., Swatton, J.E., Wayland, M.T., Holland, A.J., Bahn, S.·2007·Genomics
DOI 10.1016/j.ygeno.2007.08.005
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Abstract

The mechanisms by which trisomy 21 leads to the characteristic Down syndrome (DS) phenotype are unclear. We used whole genome microarrays to characterize for the first time the transcriptome of human adult brain tissue (dorsolateral prefrontal cortex) from seven DS subjects and eight controls. These data were coanalyzed with a publicly available dataset from fetal DS tissue and functional profiling was performed to identify the biological processes central to DS and those that may be related to late onset pathologies, particularly Alzheimer disease neuropathology. A total of 685 probe sets were differentially expressed between adult DS and control brains at a stringent significance threshold (adjusted p value (q) < 0.005), 70% of these being up-regulated in DS. Over 25% of genes on chromosome 21 were differentially expressed in comparison to a median of 4.4% for all chromosomes. The unique profile of up-regulation on chromosome 21, consistent with primary dosage effects, was accompanied by widespread transcriptional disruption. The critical Alzheimer disease gene, APP, located on chromosome 21, was not found to be up-regulated in adult brain by microarray or QPCR analysis. However, numerous other genes functionally linked to APP processing were dysregulated. Functional profiling of genes dysregulated in both fetal and adult datasets identified categories including development (notably Notch signaling and Dlx family genes), lipid transport, and cellular proliferation. In the adult brain these processes were concomitant with cytoskeletal regulation and vesicle trafficking categories, and increased immune response and oxidative stress response, which are likely linked to the development of Alzheimer pathology in individuals with DS.

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  • Prior transcriptome studies of DS brains or derived pluripotent stem cells are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation.

    “While several reports have investigated gene expression in postmortem human DS brains or derived pluripotent stem cells (Letourneau et al., 2014; Lockstone et al., 2007; Mao et al., 2003, 2005), these studies are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation.”

    From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Lockstone et al., 2007

    The Abstract (page not provided) reports seven adult DS subjects and eight controls, and the Comparison with fetal DS brain section notes that the small fetal dataset reduced statistical power. The paper thus supports a sample-number limitation, but it used whole-genome microarrays, and its postmortem-brain study does not address differences between in vitro and in vivo gene regulation. (LLM, conf=0.85)

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  • Many genes throughout the genome are altered in DS, confirming and extending previous findings that non-HSA21 genes may contribute significantly to trisomy 21 phenotypes.

    “Together, these studies demonstrate that many genes throughout the genome are altered in DS, confirming and extending previous findings that non-HSA21 genes may contribute significantly to trisomy 21 phenotypes (Letourneau et al., 2014; Lockstone et al., 2007).”

    From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Lockstone et al., 2007

    The Discussion (page not available in our copy) reports numerous transcriptional changes throughout the genome in adult Down syndrome brain, supporting the claim that altered genes extend beyond chromosome 21. It does not establish that non-chromosome-21 genes contribute significantly to Down syndrome phenotypes; it cautions that the wider changes could instead be effects of defects and pathologies associated with Down syndrome. (LLM, conf=0.82)

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  • Quantification of both mRNA and protein levels in brains of individuals with DS from fetal to adult stages have shown that not all trisomic genes are dysregulated or expressed at 1.5-fold.

    “Quantification of both mRNA and protein levels in brains of individuals with DS from fetal to adult stages have shown that not all trisomic genes are dysregulated or expressed at 1.5-fold (Lockstone et al., 2007; Mao et al., 2005; Mao et al., 2003).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Lockstone et al., 2007

    The Discussion (page unavailable) reports that only a subset of chromosome 21 genes was up-regulated in adult Down syndrome brain and that adult mRNA increases sometimes exceeded 1.5-fold. It also says fetal-brain mRNA up-regulation fit the 1.5-fold model. The paper discusses protein findings from a parallel study, but does not establish the claim about protein levels across fetal-to-adult stages. (LLM, conf=0.86)

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Authors
Lockstone, H. E., Harris, L. W., Swatton, J. E., Wayland, M. T., Holland, A. J., & Bahn, S.
Affiliations
University of Cambridge (GB)
Corresponding author
Bahn, S.
ORCID
Venue
Genomics
Publisher
Elsevier BV
Published
2007-12
Volume
90
Issue
6
Pages
647-660
ISSN
0888-7543 (ISSN-L)
DOI
10.1016/j.ygeno.2007.08.005
OpenAlex
W2010597204
Cited by
240
References
76
Citations by year
2026: 6 · 2025: 14 · 2024: 10 · 2023: 8 · 2022: 13 · 2021: 20 · 2020: 12 · 2019: 14 · 2018: 15 · 2017: 14 · 2016: 15 · 2015: 11 · 2014: 16 · 2013: 15 · 2012: 19
FWCI
9.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Genomics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Stanley Medical Research Institute
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Down syndrome, dorsolateral prefrontal cortex, gene expression profiling, APP processing, Notch signaling, Dlx genes, lipid transport, cell proliferation, cytoskeleton regulation, vesicle trafficking, immune response, oxidative stress response
MeSH terms
Adult, Aged, Alzheimer Disease, Chromosomes, Human, Pair 21, Down Syndrome, Female, Fetus, Humans, Male, Middle Aged, Receptors, Cell Surface, Up-Regulation, Case-Control Studies, Polymerase Chain Reaction, Amyloid beta-Protein Precursor, Prefrontal Cortex, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Databases, Genetic, Proteomics, Protease Nexins

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