Alzheimer's Disease Amyloid-β Links Lens and Brain Pathology in Down Syndrome
| Autor: | Anca Mocofanescu, Suqian Lu, Mark Burton, Joy Ghosh, Richard M. Robb, Lee E. Goldstein, Maria Ericsson, Jer R. Kuszak, Rudolph E. Tanzi, Roberto Pineda, Robert D. Moir, Juliet A. Moncaster, Stephanie J. Soscia, Rebecca D. Folkerth, David G. Hunter, John I. Clark |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Aging Pathology Light lcsh:Medicine Lens protein 0302 clinical medicine Amyloid precursor protein Scattering Radiation Child lcsh:Science Aged 80 and over Multidisciplinary Ophthalmology/Cataracts and Other Lens Disorders biology Molecular pathology P3 peptide Brain Middle Aged Pathology/Molecular Pathology 3. Good health Fiber cell Child Preschool Neurological Disorders/Cognitive Neurology and Dementia Lens disorder Female Alzheimer's disease Neurological Disorders/Alzheimer Disease Research Article Adult medicine.medical_specialty Adolescent Molecular Sequence Data Neuropathology Cataract Young Adult 03 medical and health sciences Alzheimer Disease Lens Crystalline mental disorders medicine Humans Amino Acid Sequence Eye Proteins Protein Structure Quaternary Aged Amyloid beta-Peptides lcsh:R medicine.disease 030221 ophthalmology & optometry biology.protein lcsh:Q Down Syndrome 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE, Vol 5, Iss 5, p e10659 (2010) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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 (Abeta), 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 Abeta 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 Abeta 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 Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 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 Abeta in DS lenses. Incubation of synthetic Abeta 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 Abeta accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD. |
| Databáze: | OpenAIRE |
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