title: Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta 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 beta-amyloid (Abeta). Here we demonstrate that Alzheimer's precursor protein (betaAPP) 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 betaAPP expression, increased in the monkey lenses treated with H2O2, UV radiation, or phorbol 12-myristate 13-acetate and paralleled the increase in betaAPP expression. Rat lenses exposed to oxidative stress showed increased betaAPP in the anterior epithelium and cortex. Incubation of cultured rabbit lens N/N1003A epithelial cells with Abeta induced inclusions and vacuoles and was cytotoxic. Abeta cross-reacting protein was readily detected in the cortex of a cataractous human lens. Our data show that betaAPP and Abeta 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.
authors.affiliation: Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Frederikse
authors.forename: D
authors.initials: D
authors.lastname: Garland
authors.forename: J S
authors.initials: JS
authors.lastname: Zigler
authors.forename: J
authors.initials: J
authors.lastname: Piatigorsky
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004847:Epithelial Cells; D015870:Gene Expression; D007150:Immunohistochemistry; D007908:Lens, Crystalline / Q000166:cytology / Q000378:metabolism*; D008253:Macaca mulatta; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D012333:RNA, Messenger; D018808:Transcription Factor AP-1