UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Mumford, Paige; Tosh, Justin; Anderle, Silvia; Wikberg, Eleni Gkanatsiou; Lau, Gloria; Noy, Sue; Cleverley, Karen; ... Wiseman, Frances K; + view all (2022) Genetic mapping of APP and amyloid-β biology modulation by trisomy 21. Journal of Neuroscience , 42 (33) pp. 6453-6468. 10.1523/JNEUROSCI.0521-22.2022. Green open access

[thumbnail of JNEUROSCI.0521-22.2022.full.pdf]
Preview
Text
JNEUROSCI.0521-22.2022.full.pdf - Accepted Version

Download (6MB) | Preview

Abstract

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer's disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-β accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/amyloid-β in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2 Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS, compared to those who have familial AD caused by triplication of APP Significance Statement:Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease, which has been previously attributed to people with Down syndrome having three copies of the APP gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al. 2018, Brain; Tosh et al. 2021 Scientific Reports). Here, we use a mapping approach to narrow-down the genetic cause of the modulation of pathology; demonstrating that gene(s) on chromosome 21 decrease amyloid-β accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.

Type: Article
Title: Genetic mapping of APP and amyloid-β biology modulation by trisomy 21
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.0521-22.2022
Publisher version: https://doi.org/10.1523/JNEUROSCI.0521-22.2022
Language: English
Additional information: This version is the author accepted manuscript. For the purpose of open access, the author has applied a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Keywords: Amyloid precursor protein (APP), amyloid-β, Down syndrome, DYRK1A, BACE2
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10152417
Downloads since deposit
424Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item