Cataracts Contain Amyloid β-Sheets: A 2D IR Study of Human Cataract Tissue

Abstract

Age-related cataract disease affects the sight of more than 50% of Americans over the age of 80. Cataracts are caused by the aggregation of crystallin proteins in the eye lens, leading to blurred vision, but there is not a clear understanding of the molecular structure changes that lead to the disease. In vitro, crystallin proteins form both amorphous aggregates and amyloid fiber structures, depending on the solution conditions; however, there is little evidence that the aggregates in cataractous lens tissue contain amyloid deposits. This talk will present two-dimensional infrared (2D IR) spectra of natural human cataract lens tissue collected from a deceased individual. 2D IR spectra distinguish between the native β-sheet structures of crystallin lens proteins and their amyloid fiber aggregates through a distinct diagonal peak as well as an off-diagonal cross peak. Control experiments are presented on in vitro crystallin proteins, pig lens tissue, and human non-cataract lens tissue for comparison with diagnosed cataract lens tissue spectra. The 2D IR signatures of amyloid β-sheets are clearly observed in cataract tissue. We also show that exposure to UV radiation, a significant risk factor for age-related cataract disease, produces signatures of amyloid formation in healthy eye lens tissue. These results establish cataracts as an amyloid disease, and have implications for the recent development of small molecules that appear to dissolve cataracts in animal models.