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.

Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

“…App NL-F mouse model Following on from our previous studies, which indicated that an additional copy of Hsa21 alters APP biology and the accumulation of amyloid-β in vivo in an APP transgenic model [8,9], here we determined if an additional copy of Hsa21 modulated APP/amyloid-β biology in the App NL-F knock-in mouse model. We undertook a two generation cross of the Tc1 mouse model of DS [18], which contains a freely segregating copy of Hsa21 (but not a functional additional copy of APP) [23], with the App NL-F model to generate 4 genotypes of mice (wild-type, Tc1, App NL-F/NL-F and Tc1;App NL-F/NL-F ).…”

“…The high prevalence of AD in DS is in part due to the gene encoding amyloid precursor protein (APP) being located on Hsa21, thereby raising APP and amyloid-β protein levels [4][5][6]. Recent studies in preclinical systems have demonstrated that an extra copy of other genes on Hsa21 can modulate APP biology [7][8][9][10] and thus may alter the earliest stages of AD in individuals who have DS. These extra genes may act to promote or to reduce amyloid-β accummulation and which mechanism predominates is currently unclear.…”

From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum

“…In addition to neurodevelopmental disorders discussed earlier in this review, Down syndrome (DS), which results from trisomy of human chromosome 21, is a cause of early onset Alzheimer's disease-dementia (AD-DS) (Ballard et al, 2016;Tosh et al, 2021). Two-thirds of individuals with DS will develop dementia by the age of 65 (Tosh et al, 2021).…”

“…In rodent studies of DS-AD, triplication of chromosome 21 genes other than APP demonstrated increased Aβ aggregation deposition and cognitive deficits (Wiseman et al, 2018). A recent study, focused on a model of DS comprising of a mutation in a Down syndrome critical region (Hsa21) on chromosome 21 encompassing 21q21-21q22.3 (Li et al, 2016;Tosh et al, 2021). This study crossed an Hsa21 mouse model of DS with partial trisomies other than APP with a transgenic APP mouse model and revealed that an additional copy of genes of the Hsa21 region modulates APP/Aβ biology, including Aβ aggregation and mortality (Tosh et al, 2021).…”

“…A recent study, focused on a model of DS comprising of a mutation in a Down syndrome critical region (Hsa21) on chromosome 21 encompassing 21q21-21q22.3 (Li et al, 2016;Tosh et al, 2021). This study crossed an Hsa21 mouse model of DS with partial trisomies other than APP with a transgenic APP mouse model and revealed that an additional copy of genes of the Hsa21 region modulates APP/Aβ biology, including Aβ aggregation and mortality (Tosh et al, 2021). Despite striking similarities between AD and DS in terms of genetics and symptoms onset, neurovascular impairments in DS have been largely overlooked.…”