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 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.

Reduction of Cystatin B results in increased cathepsin B activity in disomic but not Trisomy21 human cellular and mouse models

“…Duplication of the Hsa21-located APP gene that encodes amyloid precursor protein (APP) causes an overproduction of amyloid-β, triggering its accumulation in the brain [5]. In addition, an extra copy of Hsa21 genes other than APP, also modulates the generation and accumulation of amyloid-β [6][7][8][9][10][11].…”