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.
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.
Frederikse
P H
PH
Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Garland
D
D
Zigler
J S
JS
Piatigorsky
J
J
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D012333:RNA, Messenger; D018808:Transcription Factor AP-1