Summary: New research shows that extra copies of genes on chromosome 21, beyond the well-known APP gene, increase Alzheimer’s-like brain changes and impair cognition in a Down syndrome mouse model. These results shed light on why people with Down syndrome often develop early-onset Alzheimer’s and point to additional genetic contributors and pathways that might be targeted to prevent or delay disease.
Source: The Francis Crick Institute.
Researchers have moved closer to identifying which genes on chromosome 21 contribute to early-onset Alzheimer’s disease in people with Down syndrome.
A team led by scientists at the Francis Crick Institute and UCL, together with international collaborators, report evidence that genes besides APP on chromosome 21 can drive Alzheimer’s-like pathology and cognitive decline in a mouse model of Down syndrome. The findings may help guide future strategies to prevent or treat Alzheimer’s in people with Down syndrome, and also improve understanding of dementia mechanisms in the wider population.
Down syndrome affects about 1 in 800 births and is caused by a third copy (trisomy) of chromosome 21. While the APP gene on chromosome 21 has long been implicated in Alzheimer’s because it encodes the amyloid precursor protein that gives rise to amyloid beta peptides, chromosome 21 carries more than two hundred genes in total. By their 60s, roughly two thirds of people with Down syndrome develop early-onset Alzheimer’s disease, suggesting that additional genes and molecular pathways may modify risk and disease progression.
Published in the journal Brain, the new study systematically separated the effect of APP from other chromosome 21 genes using carefully designed mouse models. The researchers compared mice that overproduce the APP-derived amyloid protein with mice that carry an extra copy of the entire human chromosome 21 region represented in the model. This strategy allowed the team to tease apart contributions from APP versus other triplicated genes on chromosome 21.
The results show that mice with an extra copy of all chromosome 21 genes displayed more pronounced Alzheimer’s-like features than mice that only overproduce APP. Specifically, these trisomic mice developed higher levels of amyloid-beta, increased accumulation of amyloid plaques in memory-related brain regions, and more severe impairments on behavioral tests of memory. These findings indicate that triplication of genes other than APP enhances amyloid pathology and worsens cognitive outcomes in this model.
The research team probed why amyloid-beta accumulation increased in mice with full chromosome 21 trisomy. They found a shift in the balance of amyloid-beta isoforms: trisomic mice produced more of a particular amyloid-beta variant that is more prone to clump and form plaques. Importantly, this shift in the amyloid-beta 40/42 ratio appeared to occur independent of changes in the γ-secretase complex’s carboxypeptidase activity (the enzyme complex that cleaves APP) and without detectable changes in extracellular amyloid-beta clearance rates. In other words, the presence of extra chromosome 21 genes altered amyloid processing or composition in a way that favored aggregation, distinct from classical APP overproduction or clearance defects.
Dr Frances Wiseman, Senior Research Fellow at UCL and first author, highlighted the significance: “For the first time in our model of Down syndrome, we show that genes other than APP contribute to early-onset Alzheimer’s disease. Identifying these genes and the pathways they affect in the earliest stages of neurodegeneration could open the door to interventions that prevent disease in people with Down syndrome.”
Dr Victor Tybulewicz, Group Leader at the Francis Crick Institute and co-senior author, described the technical challenges that made this work possible: “Modeling Down syndrome in mice is difficult because the human chromosome 21 genes are distributed across three different mouse chromosomes. Years of refining these models have allowed us to study Alzheimer’s onset and other disease processes in the context of trisomy.”
Elizabeth Fisher, Professor of Neurogenetics at UCL and co-senior author, added that the study’s broader value lies in its insight into early disease mechanisms: “Although we approached Alzheimer’s through the lens of Down syndrome, these findings provide new mechanistic clues about early Alzheimer’s progression that could be relevant to the general population.”
Funding: This work was supported by the Wellcome Trust Strategic Award, the Medical Research Council, Alzheimer’s Research UK, the Alzheimer’s Society, and Torsten Söderberg.
Source and Publisher: The Francis Crick Institute; coverage organized by Neuroscience News.
Image credit: Public domain image used in the original coverage.
Abstract (revised summary)
Trisomy of human chromosome 21 is the single most common genetic risk factor for early-onset Alzheimer’s disease. Individuals with Down syndrome develop the characteristic amyloid plaques and neurofibrillary tangles of Alzheimer’s disease early in life, and most will develop dementia. While triplication of APP alone is sufficient to cause early-onset Alzheimer’s, this study demonstrates in a mouse model that triplication of additional chromosome 21 genes enhances amyloid-β aggregation, increases plaque deposition, and amplifies associated cognitive deficits. The effect correlates with a change in the soluble amyloid-β 40/42 ratio, favoring the more aggregation-prone isoform, and occurs independently of altered γ-secretase carboxypeptidase activity or of extracellular amyloid-β clearance rate. These findings suggest that genes on chromosome 21 beyond APP play an important role in Alzheimer’s disease pathogenesis in people with Down syndrome and highlight new pathways that could inform therapeutic strategies.