Genetic Mapping of APP and Amyloid-β Biology Modulation by Trisomy 21
Open accessPublished version of a preprint
Abstract
Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer9s disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation (AppNL-F) to determine how chromosome 21 genes, other than APP, modulate APP/Aβ in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aβ accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aβ accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2. Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aβ in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP. SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer9s disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (APP) gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aβ accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.
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Some genes triplicated in Dp16 mice may have a protective role, attenuating some phenotypes observed in AD, including Bace2 and Cstb involved in Aβ processing and clearance.
“This suggests that some genes triplicated in Dp16 mice may also have a protective role, attenuating some phenotypes observed in AD, including Bace2 and Cstb that are involved in Aβ processing and clearance.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [62]
The Results report reduced amyloid-β accumulation in a Dp3Tyb mouse model carrying an extra copy of Bace2, and the Discussion describes BACE2 as a possible amyloid-β-degrading protease. The paper does not establish that Bace2 causes the reduction, and the passages do not address Cstb or a protective effect in Dp16 mice. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEvidence in preclinical models demonstrates that genes other than APP being in three copies modify aspects of DSAD, such as cognition and amyloid-β load.
“Evidence in preclinical models demonstrates that genes other than APP being in three copies modify aspects of DSAD, such as cognition and amyloid-β load [1, 50, 70]”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [50]
The Conclusion reports that extra copies of chromosome 21 genes reduced brain amyloid-β accumulation in mouse models, supporting the amyloid-β part of the claim. The paper does not report that its models demonstrate a change in cognition; its discussion of cognitive deficits appears in references to other work. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAn 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 [62]
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- Authors
- Mumford, P., Tosh, J., Anderle, S., Gkanatsiou Wikberg, E., Lau, G., Noy, S., Cleverley, K., Saito, T., Saido, T. C., Yu, E., Brinkmalm, G., Portelius, E., Blennow, K., Zetterberg, H., Tybulewicz, V., Fisher, E. M. C., & Wiseman, F. K.
- Affiliations
- UK Dementia Research Institute (GB)
- UCL Queen Square Institute of Neurology (GB)
- RIKEN Center for Brain Science (JP)
- Roswell Park Comprehensive Cancer Center (US)
- University of Gothenburg (SE)
- Sahlgrenska University Hospital (SE)
- The Francis Crick Institute (GB)
- Corresponding author
- Fisher, Elizabeth M.C.
- Wiseman, Frances K.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2022-07-14
- Volume
- 42
- Issue
- 33
- Pages
- 6453-6468
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC9398545
- OpenAlex
- W4285494509
- Cited by
- 22
- References
- 56
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 2 · 2023: 6 · 2022: 1
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (ADSF-21-831377-C, ZEN-21-848495, #ADSF-21-831381-C, 2021 Zenith Award, -21- 831377-C)
- Eli Lilly and Company
- Biogen
- Familjen Erling-Perssons Stiftelse (FO2019-0228, 860197)
- Wellcome Trust (098328, MR/S005145/1, 098327, FC001194, 098330/Z/12/Z, 098327/Z/12/Z)
- Francis Crick Institute (FC001194, CC 2080, 10194)
- Stiftelsen för Gamla Tjänarinnor (860197, FO2019‐0228)
- Prothena
- Alzheimer's Society
- Cancer Research UK (FC001194)
- European Commission (HORIZON2020, 860197)
- Agence Nationale de la Recherche (ANR-18-COEN-0002)
- Hjärnfonden (FO2017‑0243, FO2017, ALFGBG-715986, FO2019‐0228)
- Vetenskapsrådet (2017-00915, (#ALFGBG-715986, 681712, 2018-, FO2017-0243, 2018-02532)
- Julius Clinical
- UK Dementia Research Institute (#2017-00915, UKDRI-1014)
- Olav Thon Stiftelsen (#FO2019-0228)
- Medical Research Council (FC001194, MR/S005145/1, U117527252)
- H2020 European Research Council (681712)
- 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, early-onset Alzheimer's disease, amyloid-beta deposition, amyloid precursor protein, APP, chromosome 21, DYRK1A, BACE2, gene mapping, mouse models of Down syndrome
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Down Syndrome, Female, Humans, Male, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice
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