The retinal oxysterol pathway: a unifying hypothesis for the cause of age-related macular degeneration.
OBJECTIVE
To summarize recent findings implicating toxic agents resulting in photooxidation of cholesterol in the etiology of age-related macular degeneration. Understanding the role of these agents and the existing pathways for their neutralization may lead to novel therapeutic approaches.


RESULTS
The human eye is now known to produce significant quantities of 7-ketocholesterol and related substances as a direct result of photoreceptor function. These substances are highly toxic to retinal cells and the eye has been shown to be unique among human organs in expressing three separate enzymatic pathways that neutralize these agents. Drusen are recently shown to contain significant accumulations of 7-ketocholesterol, likely as a result of failure of these neutralization pathways. In addition to its direct tissue toxicity, which may trigger death of retinal pigment epithelium and photoreceptor cells, ketocholesterol is a potent attractor of macrophages and induces macrophages to express both vascular endothelial growth factor F and metalloproteinases. The role of the former in neovascularization is well understood, whereas the latter is capable of directly inducing breaks in Bruch's membrane.


CONCLUSIONS
The toxic role of 7-ketocholesterol and existing pathways for its neutralization may point the way to a unified theory that explains the cause of age-related macular degeneration and points towards novel therapeutic interventions.
Javitt
Norman B
NB
New York University Langone Medical Center, New York, New York, USA.
Javitt
Jonathan C
JC
D000818:Animals; D006801:Humans; D007653:Ketocholesterols / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D008268:Macular Degeneration / Q000209:etiology* / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000528:radiation effects; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007653:Ketocholesterols; D042461:Vascular Endothelial Growth Factor A; D045726:Metalloproteases; C003001:7-ketocholesterol