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

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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-b aggregation, deposition of amyloid-b 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-b aggregation correlates with an unexpected shift in soluble amyloid-b 40/42 ratio. This alteration in amyloid-b isoform ratio occurs independently of a change in the carboxypeptidase activity of the -secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-b. 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.

Original languageEnglish
Pages (from-to)2457-2474
Number of pages18
Issue number8
StatePublished - Aug 1 2018

Bibliographical note

Funding Information:
The authors are funded by a Wellcome Trust Strategic Award (grant number: 098330/Z/12/Z) awarded to The London Down Syndrome (LonDownS) Consortium (V.L.J.T., and E.M.C.F). Additionally, the authors are

Funding Information:
funded by a Wellcome Trust Joint Senior Investigators Award (V.L.J.T. and E.M.C.F.), the Medical Research Council (programme number U117527252; awarded to V.L.J.T. and programme grant G0601056 awarded to V.L.J.T and E.M.C.F), as well as by awards from Alzheimer’s Research UK (awarded to F.K.W and E.M.C.F), Alzheimer’s Society (awarded to E.M.C.F and F.K.W.), Epilepsy Research UK (awarded to F.K.W.), and the Torsten Söderberg Foundation at the Royal Swedish Academy of Sciences (awarded to K.B.). V.L.J.T. was funded by the Francis Crick Institute which receives its core funding from the Medical Research Council (FC001194), Cancer Research UK (FC001194) and the Wellcome Trust (FC001194).

Funding Information:
The authors thank Lennart Mucke (Gladstone Institute) for the J20 APP transgenic mouse model. Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK Medical Research Council (G0400074), by NIHR Newcastle Biomedical Research Centre and Unit awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and by a grant from the Alzheimer’s Society and Alzheimer’s Research Trust as part of the Brains for Dementia Research Project. We thank Oke Avwenagha for her assistance with this project.

Funding Information:
B.S., consultant for and funding from Janssen pharmaceu-tica; D.H., Co-founder C2N Diagnostic; Consults: AstraZeneca, Genentech, Lilly, Neurophage, C2N Diagnostic.

Publisher Copyright:
© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.


  • APP
  • Alzheimer’s disease
  • Amyloid-b
  • Down syndrome
  • Neurodegeneration

ASJC Scopus subject areas

  • Medicine (all)


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