Summary: Researchers report extra copies of genes on chromosome 21 increase Alzheimer’s like pathology and cognitive impairment in mouse models of Down syndrome. The findings provide insight into early onset Alzheimer’s in those with Down syndrome.
Source: The Francis Crick Institute.
Scientists are a step closer to understanding which genes are responsible for early onset Alzheimer’s disease in people with Down syndrome, thanks to a new study led by researchers at the Francis Crick Institute and UCL along with an international group of collaborators.
The findings could pave the way for future medicines to prevent the disease in these individuals, and provide insights into the mechanisms that cause dementia in the general population.
Around 1 in 800 people are born with Down syndrome, which arises in people carrying an extra copy of chromosome 21. By the time they reach their 60s, around two thirds of those with Down syndrome will have early onset Alzheimer’s.
The high rates of Alzheimer’s in people with Down syndrome were previously thought to be caused by a particular gene on chromosome 21 called APP. Chromosome 21 contains 231 genes, but APP was the prime suspect because it produces amyloid precursor proteins. These are involved in generating amyloid beta proteins, which build up in the brain in Alzheimer’s patients.
In this study, published in the journal Brain, researchers found that extra copies of other genes on chromosome 21 increase Alzheimer’s-like brain pathology and cognitive impairments in a mouse model of Down syndrome.
Dr Frances Wiseman, Senior Research Fellow at UCL, and first author of this study, said: “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. 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.”
The team compared mice that produce APP amyloid protein with, and without, the presence of human chromosome 21, to tease apart the contributions of APP and other genes in Alzheimer’s disease.
They found that mice with an extra copy of all the genes on chromosome 21 had more signs of Alzheimer’s disease than mice without. The mice with extra copies of all genes on chromosome 21 had greater levels of amyloid beta and more protein clumps or ‘plaques’ inside part of the brain that controls memory, and performed worse on memory tests.
The team then looked at what was causing the increased build-up of amyloid-beta and plaques in the brains of mice with extra copies of all the genes on human chromosome 21. They found that these mice produced more of a particular type of amyloid beta protein that is more prone to forming clumps.
Dr Victor Tybulewicz, Group Leader at the Francis Crick Institute and co-senior author of the paper, said: “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. 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.”
Elizabeth Fisher, Professor of Neurogenetics at UCL, and co-senior author of the paper, added: “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.”
About this neuroscience research article
Funding: This research was supported by the Wellcome Trust Strategic Award, Medical Research Council, Alzheimer’s Research UK, Alzheimer’s Society, Torsten Söderber.
Source: Greta Keenan – The Francis Crick Institute Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is in the public domain. Original Research: Open access research for “Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP” by Frances K Wiseman, Laura J Pulford, Chris Barkus, Fan Liao, Erik Portelius, Robin Webb, Lucia Chávez-Gutiérrez, Karen Cleverley, Sue Noy, Olivia Sheppard, Toby Collins, Caroline Powell, Claire J Sarell, Matthew Rickman, Xun Choong, Justin L Tosh, Carlos Siganporia, Heather T Whittaker, Floy Stewart, Maria Szaruga, London Down syndrome consortium, Michael P Murphy, Kaj Blennow, Bart de Strooper, Henrik Zetterberg, David Bannermank David M Holtzman, and Victor L J Tybulewicz in Brain. Published June 26 2018. doi:10.1093/brain/awy159
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[cbtabs][cbtab title=”MLA”]The Francis Crick Institute”Genes Linking Alzheimer’s to Down Syndrome Discovered.” NeuroscienceNews. NeuroscienceNews, 26 June 2018. <https://neurosciencenews.com/alzheimers-down-genetics-9448/>.[/cbtab][cbtab title=”APA”]The Francis Crick Institute(2018, June 26). Genes Linking Alzheimer’s to Down Syndrome Discovered. NeuroscienceNews. Retrieved June 26, 2018 from https://neurosciencenews.com/alzheimers-down-genetics-9448/[/cbtab][cbtab title=”Chicago”]The Francis Crick Institute”Genes Linking Alzheimer’s to Down Syndrome Discovered.” https://neurosciencenews.com/alzheimers-down-genetics-9448/ (accessed June 26, 2018).[/cbtab][/cbtabs]
Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APPs
Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer’s disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer’s disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer’s disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer’s disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer’s disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.