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@article{Wiseman:2018:brain/awy159,
author = {Wiseman, FK and Pulford, LJ and Barkus, C and Liao, F and Portelius, E and Webb, R and Chávez-Gutiérrez, L and Cleverley, K and Noy, S and Sheppard, O and Collins, T and Powell, C and Sarell, CJ and Rickman, M and Choong, X and Tosh, JL and Siganporia, C and Whittaker, HT and Stewart, F and Szaruga, M and London, Down syndrome consortium and Murphy, MP and Blennow, K and de, Strooper B and Zetterberg, H and Bannerman, D and Holtzman, DM and Tybulewicz, VLJ and Fisher, EMC},
doi = {brain/awy159},
journal = {Brain},
pages = {2457--2474},
title = {Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP},
url = {http://dx.doi.org/10.1093/brain/awy159},
volume = {141},
year = {2018}
}

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TY  - JOUR
AB  - 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.
AU  - Wiseman,FK
AU  - Pulford,LJ
AU  - Barkus,C
AU  - Liao,F
AU  - Portelius,E
AU  - Webb,R
AU  - Chávez-Gutiérrez,L
AU  - Cleverley,K
AU  - Noy,S
AU  - Sheppard,O
AU  - Collins,T
AU  - Powell,C
AU  - Sarell,CJ
AU  - Rickman,M
AU  - Choong,X
AU  - Tosh,JL
AU  - Siganporia,C
AU  - Whittaker,HT
AU  - Stewart,F
AU  - Szaruga,M
AU  - London,Down syndrome consortium
AU  - Murphy,MP
AU  - Blennow,K
AU  - de,Strooper B
AU  - Zetterberg,H
AU  - Bannerman,D
AU  - Holtzman,DM
AU  - Tybulewicz,VLJ
AU  - Fisher,EMC
DO  - brain/awy159
EP  - 2474
PY  - 2018///
SN  - 1460-2156
SP  - 2457
TI  - Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP
T2  - Brain
UR  - http://dx.doi.org/10.1093/brain/awy159
UR  - https://www.ncbi.nlm.nih.gov/pubmed/29945247
UR  - http://hdl.handle.net/10044/1/60437
VL  - 141
ER  -

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