Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
The Francis Crick Institute, London, NW1 1AT, UK.
Sci Rep. 2021 Mar 11;11(1):5736. doi: 10.1038/s41598-021-85062-3.
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.
患有唐氏综合征（由 21 号染色体三体引起）的个体患早发性阿尔茨海默病的风险大大增加，在这种疾病中，淀粉样蛋白-β在大脑中积累。淀粉样蛋白-β是 21 号染色体基因 APP（淀粉样前体蛋白）的产物，额外的 APP 拷贝或“剂量”被认为是导致这种早发性阿尔茨海默病的原因。然而，当唐氏综合征患者的 21 号染色体存在三个拷贝时，其他 21 号染色体基因可能会调节疾病。在这里，我们表明除了 APP 之外，21 号染色体的额外基因拷贝会影响 APP/Aβ 生物学。我们将唐氏综合征小鼠模型与部分三体杂交，得到 APP 转基因模型，发现除了改变淀粉样前体蛋白丰度外，21 号染色体基因的亚组的额外拷贝还会调节淀粉样蛋白-β聚集和 APP 转基因相关的死亡率。因此，除了 APP 之外，21 号染色体上的基因可能会调节唐氏综合征患者的阿尔茨海默病。
