Gene expression profiling in the adult Down syndrome brain

Topic: Brain proteins, microglia and lab models

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.

@article{lockstone2007-17950572,
  author  = {Lockstone, H. E. and Harris, L. W. and Swatton, J. E. and Wayland, M. T. and Holland, A. J. and Bahn, S.},
  title   = {{Gene expression profiling in the adult Down syndrome brain}},
  journal = {Genomics},
  year    = {2007},
  doi     = {10.1016/j.ygeno.2007.08.005},
  pmid    = {17950572},
  url     = {https://doi.org/10.1016/j.ygeno.2007.08.005}
}

Key findings

• 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.

Why it matters

This study compared gene activity in adult brains of people with Down syndrome and controls, finding widespread changes but not increased activity of the APP gene. It identified other genes linked to APP processing that were changed, but these are observations and not a treatment or cure.

Study details

• Participants685
• Effect size4.4%
• Evidence strengthLow

Read the original

• DOI: 10.1016/j.ygeno.2007.08.005
• PubMed: 17950572
• Original source →
• Free full text: Genomics →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy Nature genetics · 2005-12-20 · usefulness score 58/100 · Brain tissue and pathology
• Molecular mapping of Alzheimer-type dementia in Down's syndrome Annals of neurology · 1998-03-01 · usefulness score 54/100 · Risk genes beyond APOE
• APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy Brain : a journal of neurology · 2006-08-18 · usefulness score 54/100 · Brain tissue and pathology
• Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing Journal of the Royal Statistical Society Series B (Statistical Methodology) · 1995-01-01 · usefulness score 52/100 · Laboratory science
• Apolipoprotein E and Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1995-05-01 · usefulness score 50/100 · Genetics
• Trisomy 21 and the brain Journal of neuropathology and experimental neurology · 2004-07-01 · usefulness score 40/100 · Down syndrome and Alzheimer's
• Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2005-09-01 · usefulness score 34/100 · Down syndrome and Alzheimer's

Later studies that cite this one

7 studies in the alzhub library list this one in their references.

• Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome Redox biology · 2019-03-09 · usefulness score 45/100 · Down syndrome and Alzheimer's
• mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia Free radical biology & medicine · 2017-08-12 · usefulness score 45/100 · Down syndrome and Alzheimer's
• Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome Molecular neurobiology · 2025-11-21 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Endosome Dysregulation in Down Syndrome: A Potential Contributor to Alzheimer Disease Pathology Annals of neurology · 2021-02-25 · usefulness score 41/100 · Down syndrome and Alzheimer's
• Large-scale organoid study suggests effects of trisomy 21 on early fetal neurodevelopment are more subtle than variability between isogenic lines and experiments Frontiers in neuroscience · 2023-02-03 · usefulness score 39/100 · Down syndrome and Alzheimer's
• A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer’s disease and aging research bioRxiv · 2024-04-23 · usefulness score 16/100 · Down syndrome and Alzheimer's
• Modeling Down syndrome neurodevelopment with isogenic cerebral organoids bioRxiv · 2022-05-26 · usefulness score 16/100 · Down syndrome and Alzheimer's

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• Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention Journal of Alzheimer's disease : JAD · 2007-03-01 · usefulness score 41/100
• The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons Stem cell reports · 2018-05-31 · usefulness score 44/100
• Expression of human Cu-Zn superoxide dismutase gene in transgenic mice: model for gene dosage effect in Down syndrome Free radical research communications · 1991-01-01 · usefulness score 37/100
• Protein expression in Down syndrome brain Amino acids · 2001-12-01 · usefulness score 39/100
• Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain Colombia medica (Cali, Colombia) · 2014-10-01 · usefulness score 32/100

Also tagged “down”

527 studies in the library carry the topic tag “down”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 527 tagged studies.

• Genetic studies support a neuronal origin for the beta amyloid polypeptide Neurobiology of aging · 1989-09-01 · usefulness score 32/100 · Down syndrome and Alzheimer's
• Human ETS2 gene on chromosome 21 is not rearranged in Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1988-10-01 · usefulness score 34/100 · Down syndrome and Alzheimer's
• [Alzheimer-type dementia and Down syndrome] Ugeskrift for laeger · 1995-02-01 · usefulness score 26/100 · Down syndrome and Alzheimer's

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More on Down syndrome and Alzheimer's

• A review that covers this ground DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome Frontiers in behavioral neuroscience · 2016-06-03 · usefulness score 40/100
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• Newest in this subject Memory and Plasma pTau217 Refine Prognosis in Down Syndrome Annals of neurology · 2026-10-02 · Peer-reviewed · usefulness score 47/100

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