(Note: Emphasis in all quotes are ours)
The Eyes Have It. C. Seydel. Science's SAGE KE (30 October 2002)
"When junk builds up between the retina and its neighboring
layer, blindness often follows. To find a way to preserve sight, researchers
have now sifted through the deposits, called drusen, looking for clues to
their origin. Crabb and colleagues developed a way to isolate drusen and
analyze their makeup. (Crabb et al. Proc. Natl. Acad. Sci. U.S.A. 2002;
99(23):14682-7 ) The results provide the first molecular
evidence that oxidative damage fuels drusen formation and contributes to
age-related blindness."
"Light bombards the retina, and the blood flowing through it teems
with oxygen, providing ample opportunity for oxidation. Furthermore,
antioxidants sometimes hinder the disease, and smoking, which causes
oxidative damage in many tissues, increases risk of AMD. ... The
current work establishes that oxidized products collect in drusen."
"these observations...corroborate the dependence of A2-PE formation on light-induced release of all-trans-retinal and underscore the association between light exposure and the accumulation of lipofuscin by RPE cells."
"The phototoxic properties of A2-E were determined by exposing
A2-E-free and A2-E-fed RPE cell cultures to short wavelength visible light (400-500 nm)
and assessing cell viability and lysosomal integrity....Exposure of A2-E-fed cells to
light resulted in a significant loss of cell viability by 72 hours, which was not observed
in either RPE cells maintained in the dark or A2-E-free cultures exposed to light.
Toxicity was associated with a loss of lysosomal integrity.
CONCLUSIONS: A2-E is detrimental to RPE cell function by a variety of mechanisms:
inhibition of lysosomal degradative capacity, loss of membrane integrity, and
phototoxicity. Such mechanisms could contribute to retinal aging as well as retinal
diseases associated with excessive lipofuscin accumulation -for example, Age-Related
Macular Degeneration and Stargardt's disease."
"Drusen are also an early hallmark of age-related macular
degeneration (AMD). ... Epidemiologic data support a role for oxidative
damage in the etiology of AMD, and the high local oxygen tension and
exposure to light result in a highly prooxidative environment in the
retina."
"The photoreceptors lack a direct blood supply and rely on the RPE
for nutrient supply and waste removal. Abnormal accumulation of EFEMP1
between the RPE and Bruch's membrane, or within Bruch's membrane, may
create a physical barrier to transport between the RPE and the choroidal
blood supply, resulting in the additional accumulation of other molecules,
thereby forming drusen and other sub-RPE deposits."
"The retinal pigment epithelium (RPE) is a single layer of post-mitotic cells, which functions both as a selective barrier to and a vegetative regulator of the overlying photoreceptor layer, thereby playing a key role in its maintenance. Through the expression and activity of specific proteins, it regulates the transport of nutrients and waste products to and from the retina, it contributes to outer segment renewal by ingesting and degrading the spent tips of photoreceptor outer segments, it protects the outer retina from excessive high-energy light and light-generated oxygen reactive species and maintains retinal homeostasis through the release of diffusible factors."
"The ageing characteristics of the RPE suggest that in addition to cell loss, ... significant metabolic changes occur resulting, at least in part, from the intracellular accumulation of lipofuscin. This pigment has been shown to be highly phototoxic and has been linked to several oxidative changes, some leading to cell death. While the aetiology of age-related macular degeneration is complex and is as yet unresolved, it is likely that accelerated ageing-like changes in the RPE play a fundamental role in the development of this condition."
"Once the protection from the antioxidant system has been overwhelmed, apoptosis can be triggered by a mechanism involving the mitochondrial signalling. Accumulation of sublethal oxidative injury potentiates oxidative injury in affected RPE cells"
"It is well established that the retina undergoes several decremental functional and structural changes with age, and it has been suggested that most of these age-related changes may be mainly due to oxidative stress through light-induced mechanisms."
"Drusen that reach a critical size can be viewed by the
ophthalmologist. They are believed by many to be the first indication of
impending AMD"
"Photoreceptor outer segments live in a potentially toxic
environment that includes high oxygen and high photon flux. These
conditions are conducive to photooxidative damage, and the production of
byproducts of lipid peroxidation such as malondialdehyde, which can cross
link proteins."
"Thus for both drusen and for lipofuscin methods compementary to
genomics have been applied in a creative manner in the quest for an
understanding of the biogenesis of drusen and lipofuscin and their
relationship to AMD."
"Our work establishes a molecular link between oxidative damage and AMD", says John Crabb, who led the study. "We have found that protein modifications exist in drusen, including crosslinks and other modifications that can be generated from the oxidation of lipids and carbohydrates."
Note: more recent references can be found in the section marked - For Therapists...