Aβ in the Lens of the Eye: A Noninvasively Detectable Early Biomarker of Alzheimer’s Disease β‐Amyloidopathy in Humans and Transgenic Mouse Model

Abstract

AbstractBackgroundAmyloid‐ß (Aß) accumulation in brain is an early hallmark of Alzheimer’s disease (AD). We discovered Aß deposition, ß‐amyloidopathy, and colocalizing supranuclear cataracts (SNC) in lenses from people with AD (Goldstein LE et al., Lancet, 2003) and Down syndrome (DS; Moncaster JA et al., PLoS One, 2010), but not other neurodegenerative diseases or normal aging. These findings spurred development of an investigational drug‐device lens Aß eye scanner (Sapphire II, Cognoptix) that combines an Aß‐binding fluorescent ligand (Aftobetin) and specialized laser scanning ophthalmoscope for noninvasive measurement of lens Aß (FDA Breakthrough Device, 2021). Early clinical results indicate that lens Aß is an ideal biomarker for early AD detection. Here, we investigated Aß accumulation and amyloidopathy in lens and brain.MethodTg2576 transgenic (Tg+) mice express Swedish mutant human amyloid precursor protein (hAPP‐Swe), human Aß (hAß), ß‐amyloidopathy, and cognitive deficits (Hsiao et al., Science, 1996). Non‐transgenic (Tg–) littermates were used as controls. Lenses were examined by ex vivo lens stereomicroscopy. Brains and lenses were analyzed by Aß immunohistochemistry, amyloid histopathology, anti‐Aß immunogold electron microscopy, tryptic digest mass spectrometry, anti‐hAß ELISA/immunoblotting. Quasi‐elastic light scattering hAß‐lens protein aggregation analysis.ResultTg2576 Tg+ mice, but not Tg– controls, age‐dependently express hAPP, accumulate hAß, and develop hAß molecular pathology in the lens and exhibit age‐dependent Aß supranuclear opacification that recapitulates lens pathology and SNC phenotype expression in human AD and DS. We detected hAß in conditioned medium from Tg+ but not Tg– lens explant cultures. hAß potently promotes mouse lens protein aggregation in vitro.ConclusionThese results support mechanistic (genotype‐phenotype) linkage between age‐dependent Aß pathology and AD‐related phenotypes in lens and brain. Collectively, our findings identify Aß pathology as the shared molecular etiology of age‐dependent supranuclear 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 Aß pathology outside the brain and support lens Aß as an optically‐accessible biomarker for early detection and longitudinal monitoring of AD.