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

Abstract

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 β-amyloid (Aβ). Here we demonstrate that Alzheimer's precursor protein (βAPP) and Aβ 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 βAPP expression, increased in the monkey lenses treated with H2O2, UV radiation, or phorbol 12-myristate 13-acetate and paralleled the increase in βAPP expression. Rat lenses exposed to oxidative stress showed increased βAPP in the anterior epithelium and cortex. Incubation of cultured rabbit lens N/N1003A epithelial cells with Aβ induced inclusions and vacuoles and was cytotoxic. Aβ cross-reacting protein was readily detected in the cortex of a cataractous human lens. Our data show that βAPP and Aβ 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.