Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (A beta) in mammalian lenses, and A beta has toxic effects on lens epithelial cells

Many amyloid diseases are characterized by protein aggregations linked to oxidative stress. Such diseases including those of the brain, muscle, and blood vessels exhibit plaques containing beta-amyloid (A beta). Here we demonstrate that Alzheimer's precursor protein (beta APP) and A beta are present at low levels in normal lenses and increase in intact cultured monkey lenses treated with H2O2 or UV radiation (known cataractogenic agents), and with phorbol 12-myristate 13-acetate. AP-1 factor binding, shown by others to up-regulate beta APP expression, increased in the monkey lenses treated with H2O2, UV radiation, or phorbol 12-myristate 13-acetate and paralleled the increase in beta APP expression. Rat lenses exposed to oxidative stress showed increased beta APP in the anterior epithelium and cortex. Incubation of cultured rabbit lens N/N1003A epithelial cells with A beta induced inclusions and vacuoles and was cytotoxic. A beta cross-reacting protein was readily detected in the cortex of a cataractous human lens. Our data show that beta APP and A beta increase in mammalian lenses as part of a response to H2O2 or UV radiation and suggest that they may contribute to the mechanism by which oxidative damage leads to lens opacification.