Down syndrome is caused by an extra copy of chromosome 21 (trisomy 21) and represents the single most common risk factor for early-onset Alzheimer’s disease. Estimates suggest that about two-thirds of people with Down’s syndrome will have developed clinical dementia by the time they reach their 60s.
Animal studies have already shown that an extra copy of the amyloid precursor protein (APP) gene —which is sited on chromosome 21—is enough to cause early-onset Alzheimer’s disease, even in the absence of Down syndrome. Studies in mice models by a team of researchers in the U.K., Europe, and the U.S. now suggest that three copies of chromosome 21 genes other than APP may influence Alzheimer's disease pathogenesis in Down syndrome patients Their results showed that extra copies of non-APP genes are associated with increased amyloid-β (Aβ) aggregation and Aβ plaque deposition, and with worsening cognitive deficits.
The researchers hope that their findings could ultimately help lead to new treatments for Alzheimer’s disease in people with Down syndrome, but could also throw new light on the pathogenesis of Alzheimer’s disease in individuals who don’t have Down syndrome.
“We've shown for the first time that genes other than APP are playing a role in early-onset Alzheimer's disease in our model of Down syndrome,” comments Frances Wiseman, Ph.D., senior research fellow at University College London (UCL), and first author of the team’s paper, which is published today in the journal Brain. “Identifying what these genes are, and what pathways are involved in the earliest stages of neurodegeneration, could help us to one day intervene with these pathways to prevent the disease in people with Down syndrome.”
“Although we're looking at Alzheimer's disease through the lens of Down syndrome, this international collaboration provides insight into the earliest stages of disease progression, which may be applicable to modulating Alzheimer's disease in the general population,” adds Elizabeth Fisher, Ph.D., professor of neurogenetics at UCL, who is co-senior author of the paper, which is entitled “Trisomy of Human Chromosome 21 Enhances Amyloid-β Independently of an Extra Copy of APP.”
Approximately 6 million people worldwide have Down syndrome. A proportion of affected individuals will start to accumulate Aβ in their brains during childhood, and the vast majority will have Aβ accumulation by the time they are in their mid-20s. By the age of 40 years all individuals with Down syndrome will have developed neurofibrillary tangles that are similar to those developed by patients with Alzheimer’s disease in the general population, the authors explain.
While extra copies of the APP gene, even without trisomy 21, are enough to cause early-onset Alzheimer’s disease, scientists haven’t understood whether any of other 600 or more protein-coding and noncoding genetic elements on chromosome 21 might also influence disease pathogenesis in people with Down syndrome. “Understanding the genetic factors that influence amyloid-β accumulation in the context of trisomy of chromosome 21 may assist with the development of novel treatments for Alzheimer’s disease in this important population,” the authors continue.
To study this in more detail, and to investigate if trisomy of chromosome 21 sequences other than APP is enough to impact on the progression of Alzheimer’s disease, they developed a novel Down–Alzheimer’s disease rodent model by crossing a Down syndrome mouse that is aneuploidy for chromosome 21 with an Alzheimer’s disease mouse that deposits Aβ in the brain. “Thus, we have generated a new model system to understand the early stages of Down syndrome–Alzheimer’s disease, when Aβ starts to accumulate.” Importantly, the Down syndrome mouse model is trisomic for about 75% of genes on chromosome 21 and displays well-defined Down syndrome-associated deficits, “including defects in nervous system function such as in long-term potentiation, short-term memory, dendritic spine morphology, and connectivity in the hippocampus.” However, the model is “not functionally triplicated for the APP gene,” which makes it possible to study the genetic influence of Down syndrome on Alzheimer’s disease outside of APP.
“Down syndrome has historically been very difficult to model in a mouse, because the genes that we have on chromosome 21 are spread across three different chromosomes in mice, comments Victor Tybulewicz, Ph.D., group leader at the Francis Crick Institute, and co-senior author of the paper. “Only after years of refining our mouse models can we study the earliest stages of Alzheimer's, and other diseases, in the context of Down syndrome.”
The team’s initial studies confirmed that mice with an extra copy of chromosome 21 genes other than APP developed increased intracellular and extracellular deposits of Aβ in the brain, while behavioral studies showed that non-APP trisomy was also linked with worsening Aβ–associated cognitive decline, including deficits in memory. The animals were in addition less likely to survive to 15 months compared with control mice. “Thus, the chromosome 21 trisomy-associated increase in amyloid-β accumulation described here correlates with changes in multiple tests of cognition and is associated with an increased risk of mortality,” the team writes.
Interestingly, biochemical studies indicated that trisomy of chromosome 21 genes other than APP caused a change in the ratio of the Aβ peptides Aβ38, Aβ40, and Aβ42, independently of any direct effect on γ-secretase carboxypeptidase activity. Changes to γ-secretase function caused by some familial Alzheimer’s disease mutations can result in similar changes to the Aβ isoform ratios, they note. Rather, in the new mouse model, the decreased soluble Aβ40/42 ratio significantly correlated with Aβ deposition in the hippocampus of young animals. This, they suggest, indicates that “the effect of trisomy on soluble amyloid-β ratios may underlie the increased accumulation of the peptide observed within the brain.”
“Our data suggest that the increase in amyloid-β aggregation caused by trisomy of chromosome 21 may be mediated by an alteration in the ratio of soluble amyloid-β isoforms that occurs independently of alterations in the activity of α-, β-, or γ-secretases, or a change in the rate of extracellular clearance of amyloid-β,” the team concludes. They suggest that these new insights should help to direct further research. “Our work indicates that people who have Down syndrome may have exacerbated amyloid accumulation compared with individuals who have early-onset Alzheimer’s disease caused by duplication of APP,” they suggest. “Comparable pathological studies of the two causes of early-onset disease are required to investigate this hypothesis. If amyloid deposition is found to be higher in people who have Down syndrome, understanding which gene on chromosome 21 other than APP contributes to this will provide novel insights into disease development and may provide a new target for drug therapy for individuals who have Down syndrome, who are at extraordinarily high risk of developing dementia.”
Further work will also be needed to identify which proteins encoded by trisomic chromosome 21 genes influence Aβ biology in Down syndrome. The team cites prior studies that have highlighted genes including SUMP2, DYRK1A, BACE2, and CSTB, and note that other, as yet unidentified genes on chromosome 21, may affect Aβ-related processes and deposition, and mediate the effect of trisomy on Aβ ratios, aggregation and deposition. “Idenitficaiton of the causal gene(s) on chromosome 21 will provide further novel insights into the new Down syndrome–Alzheimer’s disease mechanism described in this study.”
