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

Abstract

Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimers disease, in which amyloid-{beta} accumulates in the brain. Amyloid-{beta} 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 Alzheimers 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/A{beta} 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-{beta} aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimers disease in people who have Down syndrome.