Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP
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...
| मुख्य लेखकों: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| स्वरूप: | Journal article |
| भाषा: | English |
| प्रकाशित: |
Oxford University Press
2018
|
| _version_ | 1826283223261380608 |
|---|---|
| author | Wiseman, F Pulford, L Barkus, C Liao, F Portelius, E Webb, R Chávez-Gutiérrez, L Cleverley, K Noy, S Sheppard, O Collins, T Powell, C Sarell, C Rickman, M Choong, X Tosh, J Siganporia, C Whittaker, H Stewart, F Szaruga, M London Down Syndrome Consortium Murphy, M Blennow, K De Strooper, B Zetterberg, H Bannerman, D Holtzman, D Tybulewicz, V Fisher, E LonDownS Consortium |
| author_facet | Wiseman, F Pulford, L Barkus, C Liao, F Portelius, E Webb, R Chávez-Gutiérrez, L Cleverley, K Noy, S Sheppard, O Collins, T Powell, C Sarell, C Rickman, M Choong, X Tosh, J Siganporia, C Whittaker, H Stewart, F Szaruga, M London Down Syndrome Consortium Murphy, M Blennow, K De Strooper, B Zetterberg, H Bannerman, D Holtzman, D Tybulewicz, V Fisher, E LonDownS Consortium |
| author_sort | Wiseman, F |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:55:40Z |
| format | Journal article |
| id | oxford-uuid:88004332-2895-4933-88b7-0470348438fd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:55:40Z |
| publishDate | 2018 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:88004332-2895-4933-88b7-0470348438fd2022-03-26T22:14:10ZTrisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APPJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:88004332-2895-4933-88b7-0470348438fdEnglishSymplectic Elements at OxfordOxford University Press2018Wiseman, FPulford, LBarkus, CLiao, FPortelius, EWebb, RChávez-Gutiérrez, LCleverley, KNoy, SSheppard, OCollins, TPowell, CSarell, CRickman, MChoong, XTosh, JSiganporia, CWhittaker, HStewart, FSzaruga, MLondon Down Syndrome ConsortiumMurphy, MBlennow, KDe Strooper, BZetterberg, HBannerman, DHoltzman, DTybulewicz, VFisher, ELonDownS ConsortiumDown 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. |
| spellingShingle | Wiseman, F Pulford, L Barkus, C Liao, F Portelius, E Webb, R Chávez-Gutiérrez, L Cleverley, K Noy, S Sheppard, O Collins, T Powell, C Sarell, C Rickman, M Choong, X Tosh, J Siganporia, C Whittaker, H Stewart, F Szaruga, M London Down Syndrome Consortium Murphy, M Blennow, K De Strooper, B Zetterberg, H Bannerman, D Holtzman, D Tybulewicz, V Fisher, E LonDownS Consortium Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP |
| title | Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP |
| title_full | Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP |
| title_fullStr | Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP |
| title_full_unstemmed | Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP |
| title_short | Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP |
| title_sort | trisomy of human chromosome 21 enhances amyloid β deposition independently of an extra copy of app |
| work_keys_str_mv | AT wisemanf trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT pulfordl trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT barkusc trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT liaof trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT porteliuse trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT webbr trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT chavezgutierrezl trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT cleverleyk trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT noys trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT sheppardo trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT collinst trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT powellc trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT sarellc trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT rickmanm trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT choongx trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT toshj trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT siganporiac trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT whittakerh trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT stewartf trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT szarugam trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT londondownsyndromeconsortium trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT murphym trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT blennowk trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT destrooperb trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT zetterbergh trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT bannermand trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT holtzmand trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT tybulewiczv trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT fishere trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp AT londownsconsortium trisomyofhumanchromosome21enhancesamyloidbdepositionindependentlyofanextracopyofapp |