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Cited by 26Alzheimer's disease research and treatmentsDown syndrome and intellectual disability researchDementia and Cognitive Impairment Research

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

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Tosh, Justin L., Rhymes, Elena R., Mumford, Paige, Whittaker, Heather T., Pulford, Laura J., Noy, Sue J., Cleverley, Karen, LonDownS Consortium +12 more·2021·Scientific Reports
DOI 10.1038/s41598-021-85062-3PMC PMC7952899

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Abstract

Individuals 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.

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  • Previous studies in mouse models of DS-AD have shown that independently of an extra copy of APP, other genes on HSA21 can increase Aβ plaque deposition at 5 and 6 months of age, indicating that genes act early in the pathological cascade.

    “previous studies in mouse models of DS-AD have shown that independently of an extra copy of APP, other genes on HSA21 can increase Aβ plaque deposition at 5 and 6 months of age, indicating that genes act early in the pathological cascade.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [18]

    The Introduction and Discussion report that an earlier Tc1;tgAPP mouse study found increased Aβ deposition despite the Tc1 mice lacking an extra APP copy. But the paper does not place that deposition increase at 5 and 6 months or draw the stated conclusion about its timing. Its own Results report no significant increase in plaque deposition at 6 months in the segmental-duplication models studied (page numbers unavailable). (LLM, conf=0.86)

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  • In preclinical models of DS-AD, triplication of HSA21 genes modulates Aβ aggregation and APP transgene-associated mortality independently of an extra copy of APP.

    “Importantly, it has been shown in preclinical models of DS-AD that triplication of HSA21 genes modulates Aβ aggregation and APP transgene-associated mortality independently of an extra copy of APP.17,18”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [18]

  • An additional copy of HSA21 genes can alter APP biology, including Aβ deposition, in other APP transgenic models.

    “Previous studies have indicated that an additional copy of HSA21 genes can alter APP biology, including Aβ deposition in other APP transgenic models.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [18]

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Research works printed but not linked: 26

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Authors
Tosh, J. L., Rhymes, E. R., Mumford, P., Whittaker, H. T., Pulford, L. J., Noy, S. J., Cleverley, K., LonDownS Consortium, Strydom, A., Fisher, E., Wiseman, F., Nizetic, D., Hardy, J., Tybulewicz, V., Karmiloff-Smith, A., Walker, M. C., Tybulewicz, V. L. J., Wykes, R. C., Fisher, E. M. C., & Wiseman, F. K.
Affiliations
  • The Francis Crick Institute (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • UK Dementia Research Institute (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2021-03-11
Volume
11
Issue
1
Pages
5736-5736
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-021-85062-3
PMC
PMC7952899
OpenAlex
W3135667932
Cited by
26
References
4
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 2
FWCI
2.51
Type
journal article
Language
en
Update notices
correction (2021-07-16)
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DR-NTU (Nanyang Technological University) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Alzheimer's Society
  • UCL Institute of Neurology, University College London
  • UK Dementia Research Institute (UKDRI-1014)
  • Alzheimer’s Research UK
  • Wellcome Trust (098330/Z/12/Z)
  • Epilepsy Research UK (F1401)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Down syndrome, amyloid-beta, amyloid precursor protein, APP transgenic mice, partial trisomy, Alzheimer's disease risk, amyloid-beta aggregation, genetic modifiers, mouse model
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Down Syndrome, Mice, Transgenic, Phenotype, Phosphotransferases, Protein-Arginine N-Methyltransferases, Seizures, Solubility, Survival Analysis, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Transgenes, Chromosomes, Mammalian, Mice, Segmental Duplications, Genomic, Protein Aggregates

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