Dry AMD Basic Research: Abstract and Editor's Summary from PLoS
Whole Paper with diagrams: plos.org
++++++++++++++++++++++++++++++ ABSTRACT ++++++++++++++++++++
Background
In the Western world, a major cause of blindness is age-related macular degeneration (AMD).
Recent research in angiogenesis has furthered the understanding of choroidal neovascularization,
which occurs in the ‘‘wet’’ form of AMD. In contrast, very little is known about the
mechanisms of the predominant, ‘‘dry’’ form of AMD, which is characterized by retinal atrophy
and choroidal involution. The aim of this study is to elucidate the possible implication of the
scavenger receptor CD36 in retinal degeneration and choroidal involution, the cardinal features
of the dry form of AMD.
Methods and Findings
We here show that deficiency of CD36, which participates in outer segment (OS)
phagocytosis by the retinal pigment epithelium (RPE) in vitro, leads to significant progressive
age-related photoreceptor degeneration evaluated histologically at different ages in two
rodent models of CD36 invalidation in vivo (Spontaneous hypertensive rats (SHR) and CD36/
mice). Furthermore, these animals developed significant age related choroidal involution
reflected in a 100%–300% increase in the avascular area of the choriocapillaries measured on
vascular corrosion casts of aged animals. We also show that proangiogenic COX2 expression in
RPE is stimulated by CD36 activating antibody and that CD36-deficient RPE cells from SHR rats
fail to induce COX2 and subsequent vascular endothelial growth factor (VEGF) expression upon
OS or antibody stimulation in vitro. CD36/ mice express reduced levels of COX2 and VEGF in
vivo, and COX2/ mice develop progressive choroidal degeneration similar to what is seen in
CD36 deficiency.
Conclusions
CD36 deficiency leads to choroidal involution via COX2 down-regulation in the RPE. These
results show a novel molecular mechanism of choroidal degeneration, a key feature of dry
AMD. These findings unveil a pathogenic process, to our knowledge previously undescribed,
with important implications for the development of new therapies.
+++++++++++++++EDITOR'S SUMMARY ++++++++++++++++++++++++++
Editors’ Summary
Background.
Age-related macular degeneration (AMD) is the leading
cause of blindness in the elderly in industrialized countries. The macula is
the central region of the retina, the tissue at the back of the eye that
detects light and converts it into electrical messages that are sent to the
brain. In the commonest form of AMD—‘‘dry’’ AMD—the light-sensitive
cells in the retina (the photoreceptors) gradually die. This degeneration
might occur because of damage to the retinal pigment epithelium (RPE).
This layer of dark cells lies between the photoreceptors and the choroid,
the layer of the eye that contains blood vessels and brings oxygen to the
retina. The RPE keeps the retina healthy by transferring the right amount
of oxygen and nutrients from the choroid to the retina and by removing
worn-out photoreceptor outer segments (the part of the photoreceptor
that actually absorbs light) in a process called phagocytosis (engulfment
and digestion). In addition to photoreceptor degeneration and RPE
shrinkage, a layer of the choroid rich in small blood vessels (the
choriocapillaris) also shrinks in dry AMD. For affected individuals, all
these changes (which experts describe as retinal atrophy and choroidal
involution) mean that the sharp central vision that is needed for reading
and driving is destroyed, leaving only dim, burred images or a black hole
at the center of the vision.
Why Was This Study Done?
Little is known about the molecular
mechanisms that underlie dry AMD and, consequently, there is no cure
for it. In this study, the researchers have tested whether a molecule
called CD36, which is expressed on the surface of RPE cells, is involved in
dry AMD. CD36 is a scavenger receptor—which means it binds many
potentially harmful molecules including oxidized fats (which are present
in the photoreceptor outer segments) and is involved in their
phagocytosis. Phagocytosis itself induces the expression of several
proteins in the RPE cells, including COX2, a ‘‘proangiogenic’’ protein that
stimulates the growth of blood vessels. Putting this information
together, the researchers hypothesized that a defect in CD36 might
cause the characteristic retinal atrophy (by preventing the phagocytosis
of worn-out photoreceptor outer segments) and choroidal involution (by
preventing the induction of COX2 expression and consequently the
maintenance of the blood vessels in the choroid) of dry AMD.
What Did the Researchers Do and Find? The researchers first show that
retinal degeneration occurs in rats and mice that express no CD36. This
degeneration (which included a reduction in the thickness of the retina,
the presence of irregularly shaped photoreceptor outer segments, and
the detachment of these structures from the RPE) was seen in old but
not young animals. Choroidal involution was also seen in these CD36-
deficient animals. This change was present in young mice and rats but
increased with age so that by one year old, the choriocapillaris looked
moth-eaten. Next, the researchers show that although RPE cells taken
from normal animals and grown in dishes were able to make COX2 in
response to exposure to purified photoreceptor outer segments, RPE
cells from CD36-deficient animals did not. The expression of vascular
endothelial growth factor (VEGF; a protein that is needed for normal
choroidal development and whose expression is controlled by COX2)
showed a similar pattern. Finally, the researchers report that COX2
deficiency in mice caused similar age-dependent choroidal involution
and similar effects on VEGF expression in RPE cells as CD36 deficiency.
What Do These Findings Mean?
These findings show that CD36
deficiency leads to progressive, age-related degeneration of photoreceptors
and choroidal involution in rats and mice. They also show that
CD36 deficiency causes this choroidal involution, the key feature of dry
AMD, because it leads to down-regulation of COX2 expression (and
subsequently reduced VEGF expression) in the RPE. Researchers now
need to find out whether this mechanism for the development of dry
AMD holds in people—what happens in animals does not necessarily
happen in people. If it does, pharmacological activation of CD36 or
restoration of CD36 expression in the RPE might eventually provide a
way to treat dry AMD.
Additional Information.
Please access these Web sites via the online
version of this summary at dx.doi.org .
MedlinePlus provides links to information on macular degeneration
and an encyclopedia page on macular degeneration (in English and
Spanish)
Pages on the US National Institutes of Health NIH SeniorHealth site
provides text and spoken information about AMD
The US National Eye Institute and the UK Royal National Institute of
Blind People also provide information about AMD
Wikipedia has pages on the retina, photoreceptor cells, retinal
pigment epithelium, and choroid (note that Wikipedia is a free online
encyclopedia that anyone can edit; available in several languages)
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