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

作者：Moncaster Juliet A^*; Pineda Roberto; Moir Robert D; Lu Suqian; Burton Mark A; Ghosh Joy G; Ericsson Maria; Soscia Stephanie J; Mocofanescu Anca; Folkerth Rebecca D; Robb Richard M; Kuszak Jer R; Clark John I; Tanzi Rudolph E; Hunter David G; Goldstein Lee E

来源：PLos One, 2010, 5(5): e10659.

DOI：10.1371/journal.pone.0010659

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 (similar to 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.

• 出版日期2010-5-20