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

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.

Prevalence of ocular abnormalities in adults with Down syndrome in Hong Kong

“…This figure is higher than that of the general population, where the reported prevalence of cataract was 35% for those 40 years or older among Chinese in Singapore (The Tanjong Pagar Survey) 16. Susceptibility to oxidative stress17 and the expression and accumulation of amyloid precursor protein and amyloid-β peptides 18 19 in the lens have been proposed as mechanisms for the pathogenesis of early onset cataract in DS patients. As cataract surgery is becoming safer and more efficient, screening and early treatment for visually significant cataracts may be beneficial in this population.…”

Strabismus, refractive errors and nystagmus in children and young adults with Down syndrome

“…In the most recent study, evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Aβ accumulation, co-localizing amyloidal pathology, and fiber cell cytoplasmic Aβ aggregates (~5-50 nm) identical to the lens pathology identified in Alzheimer's disease. 23 Considering the high prevalence of myopia in the age group over 20 years we propose the clinical guidelines for young adults with DS to be modified. Instead of every 5 years, 24 we recommend ophthalmologic and refractive screening every second year after 6 years of age.…”

Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice

“…Observed opacities were quantified using the Lens Opacities Classification System, version II (18 -20). For ex vivo phenotyping, eyes were dissected for lens phenotyping by ex vivo dark field photomicroscopy as described previously (21,22). For measurement of glucose levels, mice were fasted for 8 h. Glucose was measured in blood from the tail vein using the Elite system (Bayer) glucometer as described by the manufacturer.…”