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

Abstract

Purpose: : Down syndrome (DS, trisomy 21) is the leading genetic cause of intellectual disability and the most common chromosomal disorder in humans. Chromosome 21 trisomy in DS leads to increased gene dosage of the APP gene (21q21) coding for the Alzheimer’s disease (AD) amyloid precursor protein (APP), increased expression of the APP amyloid-β (Aβ) cleavage peptides, accelerated cerebral Aβ accumulation, and invariant early-onset age-dependent AD neuropathology. The DS phenotype complex also includes high-penetrance expression of distinctive early-onset cerulean cataracts of unknown etiology. We previously reported pathogenic Aβ accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the lenses of subjects with AD. Here, we investigate the hypothesis that related AD-associated Aβ lens pathology is expressed as an age-dependent early-onset lens phenotype in DS.

Methods: : Ophthalmological examinations were correlated with phenotypic, histochemical, and biochemical analyses of lenses from subjects with DS, AD, and age-matched normal controls.

Results: : Lenses from subjects with DS demonstrated lenticular Aβ accumulation, cytosolic Aβ aggregate formation, co-localizing amyloid lens pathology, and distinctive supranuclear opacification identical to that previously identified in AD. Peptide sequencing, immunoblot analysis, and ELISA demonstrated accelerated age-dependent Aβ accumulation in the lenses of subjects with DS. Incubation of synthetic Aβ with human lens protein confirmed that this amyloidogenic peptide potently promotes lens protein aggregation and dose- and time-dependently increases Rayleigh light scattering.

Conclusions: : These results define the distinctive lens phenotype in DS as a genetic cataract and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Furthermore, these data establish age-dependent Aβ accumulation as the shared molecular etiology of disease-linked pathology in the lens and brain in both DS and AD.

Keywords: pathology: human • cataract • pathobiology