Alzheimer's Disease Amyloid-\(\beta\) Links Lens and Brain Pathology in Down Syndrome

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Alzheimer's Disease Amyloid-\(\beta\) Links Lens and Brain Pathology in Down Syndrome

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Title: Alzheimer's Disease Amyloid-\(\beta\) Links Lens and Brain Pathology in Down Syndrome
Author: Moncaster, Juliet A.; Lu, Suqian; Burton, Mark A.; Ghosh, Joy G.; Soscia, Stephanie J.; Mocofanescu, Anca; Kuszak, Jer R.; Pineda, Roberto; Moir, Robert D.; Ericsson, Maria; Folkerth, Rebecca Dunn; Robb, Richard Moore; Clark, John I.; Tanzi, Rudolph Emile; Hunter, David G.; Goldstein, Lee David

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Citation: Moncaster, 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.
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Abstract: Down 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.
Published Version: doi://10.1371/journal.pone.0010659
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873949/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10198948
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