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-β peptides (Aβ), 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 Aβ 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 Aβ 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 Aβ accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Aβ aggregates (∼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 Aβ in DS lenses. Incubation of synthetic Aβ 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 Aβ accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.
Highlights
Down syndrome (DS, [1]) is the leading genetic cause of intellectual disability and the most common chromosomal disorder compatible with human survival [2,3,4,5]
Lenses from mature DS subjects demonstrated apparent age-dependent supranuclear lens pathology (Fig. 1E-H) that was phenotypically indistinguishable from that previously reported in late-onset sporadic Alzheimer’s disease (AD) (Fig. 1F-H) [28]
We identify the origin and pathogenic mechanism of cataractogenesis in DS, establish the distinctive lens phenotype in DS as a genetic cataract, and define the molecular correspondence of DS-associated pathology in the lens and brain
Summary
Down syndrome (DS, [1]) is the leading genetic cause of intellectual disability and the most common chromosomal disorder compatible with human survival [2,3,4,5]. In the majority of cases, the disorder arises from sporadic non-disjunction of chromosome 21 (HSA21) and triplication of the entire chromosome [7,8,9], or infrequently, from partial aneuploidy due to unbalanced chromosomal translocation [10,11,12,13]. Chromosomal triplication invariably includes the APP gene (21q21) that encodes the amyloid precursor protein, APP [15,16]. In DS, cerebral Ab accumulation is greatly accelerated [17] and leads to invariant early-onset AD neuropathology and age-dependent neurocognitive sequelae [18,19]
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