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dc.contributor.authorMoncaster, Juliet A.
dc.contributor.authorLu, Suqian
dc.contributor.authorBurton, Mark A.
dc.contributor.authorGhosh, Joy G.
dc.contributor.authorSoscia, Stephanie J.
dc.contributor.authorMocofanescu, Anca
dc.contributor.authorKuszak, Jer R.
dc.contributor.authorPineda, Roberto
dc.contributor.authorMoir, Robert D.
dc.contributor.authorEricsson, Maria
dc.contributor.authorFolkerth, Rebecca Dunn
dc.contributor.authorRobb, Richard Moore
dc.contributor.authorClark, John I.
dc.contributor.authorTanzi, Rudolph Emile
dc.contributor.authorHunter, David
dc.contributor.authorGoldstein, Lee David
dc.date.accessioned2013-01-18T20:10:28Z
dc.date.issued2010
dc.identifier.citationMoncaster, Juliet A., Roberto Pineda, Robert D. Moir, Suqian Lu, Mark A. Burton, Joy G. Ghosh, Maria Ericsson, et al. 2010. Alzheimer's disease amyloid-\(\beta\) links lens and brain pathology in Down syndrome. PLoS ONE 5(5): e10659.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10198948
dc.description.abstractDown syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-\(\beta\) peptides (A\(\beta\)), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased A\(\beta\) accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked A\(\beta\) pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear A\(\beta\) accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic A\(\beta\) aggregates (\(\sim\)5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of A\(\beta\) in DS lenses. Incubation of synthetic A\(\beta\) with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased A\(\beta\) accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.pone.0010659en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873949/pdf/en_US
dash.licenseLAA
dc.subjectneurological disordersen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectcognitive neurology and dementiaen_US
dc.subjectopthamologyen_US
dc.subjectcataracts and other lens disordersen_US
dc.subjectpathologyen_US
dc.subjectmolecular pathologyen_US
dc.subjectDown syndromeen_US
dc.titleAlzheimer's Disease Amyloid-\(\beta\) Links Lens and Brain Pathology in Down Syndromeen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorTanzi, Rudolph Emile
dc.date.available2013-01-18T20:10:28Z
dash.affiliation.otherHMS^Neurology-Massachusetts General Hospitalen_US
dash.affiliation.otherHMS^Cell Biologyen_US
dash.affiliation.otherHMS^Pathologyen_US
dash.affiliation.otherHMS^Neurology-Massachusetts General Hospitalen_US
dash.affiliation.otherHMS^Ophthalmologyen_US
dc.identifier.doi10.1371/journal.pone.0010659*
dash.authorsorderedfalse
dash.contributor.affiliatedGoldstein, Lee
dash.contributor.affiliatedRobb, Richard
dash.contributor.affiliatedEricsson, Maria
dash.contributor.affiliatedPineda, Roberto
dash.contributor.affiliatedFolkerth, Rebecca D.
dash.contributor.affiliatedHunter, David
dash.contributor.affiliatedMoir, Robert
dash.contributor.affiliatedTanzi, Rudolph


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