Alzheimer's disease amyloid-β pathology in the lens of the eye

Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-beta (A beta) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated A beta neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of A beta deposition, beta-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated A beta molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated A beta deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These A beta microaggregates also contain alpha B-crystallin and scatter light, thus linking A beta pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified A beta lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset A beta accumulation and A beta amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding delta-catenin, a protein that modulates A beta production in brain and lens. Here we report identification of AD-related human A beta (hA beta) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hA beta peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg(+)) mice, but not non-transgenic (Tg(-)) control mice, also express human APP, accumulate hA beta peptides, and develop hA beta molecular and ultrastructural pathologies in the lens. Tg2576 Tg(+) mice exhibit age-dependent A beta supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hA beta in conditioned medium from lens explant cultures prepared from Tg(+) mice, but not Tg(-) control mice, a finding consistent with constitutive hA beta generation in the lens. In vitro studies showed that hA beta promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between A beta pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify A beta pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related A beta pathology outside the brain and point to lens A beta as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease.