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

Tosh, JL; Rhymes, ER; Mumford, P; Whittaker, HT; Pulford, LJ; Noy, SJ; Cleverley, K; ... Wiseman, FK; + view all (2021) Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models. Scientific Reports , 11 (1) , Article 5736. 10.1038/s41598-021-85062-3. Green open access

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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.

Type: Article
Title: Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-021-85062-3
Publisher version: https://doi.org/10.1038/s41598-021-85062-3
Language: English
Additional information: © The Author(s) 2021. Tis article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Diseases of the nervous system, Genetic interaction, Genetic linkage study, Genetics of the nervous system, Neurodegenerative diseases, Neurodevelopmental disorders, Neuroscience
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10124092
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