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

• Published in: bioRxiv
• Main Authors: Justin Lee Tosh, Rhymes, Ellie, Mumford, Paige, Whittaker, Heather T, Pulford, Laura J, Noy, Sue J, Cleverley, Karen, Walker, Matthew L, Tybulewicz, Victor Lj, Wykes, Rob C, Elizabeth Mc Fisher, Wiseman, Frances K
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 20.06.2020
• Subjects: Age; Alzheimer's disease; Amyloid precursor protein; Animal models; Biology; Chromosome 21; Chromosomes; Down syndrome; Down's syndrome; Genes; Neurodegenerative diseases; Trisomy
• DOI: 10.1101/2020.06.19.162115

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. Competing Interest Statement The authors have declared no competing interest.