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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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1 University College London, Department of Neuromuscular Diseases, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
2 University College London, Department of Neuromuscular Diseases, Queen Square Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
3 University College London, The UK Dementia Research Institute, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
4 King’s College London, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); University College London, Division of Psychiatry, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
5 Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133); Nanyang Technological University, Lee Kong Chian School of Medicine, Singapore, Singapore (GRID:grid.59025.3b) (ISNI:0000 0001 2224 0361)
6 University College London, The UK Dementia Research Institute, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University College London, Reta Lila Weston Institute, Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
7 The Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); Imperial College, Department of Immunology and Inflammation, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111)
8 Birkbeck University, London, UK (GRID:grid.88379.3d) (ISNI:0000 0001 2324 0507)
9 University College London, Department of Clinical and Experimental Epilepsy, Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
10 University College London, Department of Clinical and Experimental Epilepsy, Institute of Neurology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University of Manchester, Nanomedicine Lab and the Geoffrey Jefferson Brain Research Center, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407)