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Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP.

Artikel i vetenskaplig tidskrift
Författare 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
Michael P Murphy
Kaj Blennow
Bart de Strooper
Henrik Zetterberg
David Bannerman
David M Holtzman
Victor L J Tybulewicz
Elizabeth M C Fisher
Publicerad i Brain : a journal of neurology
Volym 141
Nummer/häfte 8
Sidor 2457–2474
ISSN 1460-2156
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 2457–2474
Språk en
Länkar dx.doi.org/10.1093/brain/awy159
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Neurokemi

Sammanfattning

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.

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