Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Targeting cholesterol buildup in eye may slow age-related vision loss

03.04.2013
Targeting cholesterol metabolism in the eye might help prevent a severe form of age-related macular degeneration (AMD), one of the most common causes of blindness in older Americans, according to indications in a study in mice, which was supported by the National Institutes of Health.

Cholesterol build-up in arteries and veins, or atherosclerosis, occurs as a natural consequence of aging. Likewise, in AMD, cholesterol is known to accumulate in the eye, within deposits called drusen.


An eye affected by neovascular AMD, filled with abnormal blood vessels and yellow deposits called drusen. The white spot at the right is where the optic nerve leaves the eye.

Credit: National Eye Institute

The study, published in Cell Metabolism, shows that large cells called macrophages appear to play a key role in clearing cholesterol from the eye, and that with aging, these cells become less efficient at this task. Eye drops containing a type of drug known to promote cholesterol release from macrophages, called a liver X receptor (LXR) agonist, helped restore macrophage function and prevent AMD progression in a mouse model. The study was led by Rajendra Apte, M.D., Ph.D., a professor of ophthalmology and vision sciences at Washington University in St. Louis.

An estimated 2 million Americans have AMD. The disorder causes damage to the macula, a region of the retina responsible for central, high-resolution vision. The macula is dense with light-sensing cells called photoreceptors, and is what humans rely on for tasks that require sharp vision, such as reading, driving, and recognizing faces. This sharp vision deteriorates in AMD, which can take two forms. In one, sometimes referred to as dry AMD, vision loss is due to a gradual loss of photoreceptors in the macula. In the other, referred to as wet or neovascular AMD, abnormal blood vessels grow under the macula, leaking blood and causing rapid damage to the photoreceptors.

"This study points to a novel strategy for early intervention to prevent the progression of AMD to the severe neovascular form of the disease," said Grace Shen, Ph.D., a program director at NIH's National Eye Institute, which funded the research.

An eye doctor can detect AMD prior to vision loss by looking for drusen, which are yellow deposits under the retina that contain cholesterol and other debris. Although small drusen are a normal part of aging, larger drusen typically indicate AMD.

What triggers neovascular AMD is unclear. Drusen, and the cholesterol within them, have been prime suspects. And based on genetic studies, including a recent genome-wide association analysis (http://www.nei.nih.gov/news/pressreleases/030313.asp), the immune system appears to play a role, too. (Also see http://www.nei.nih.gov/news/pressreleases/112712.asp.) But researchers have had few details to connect these two pathways.

Dr. Apte theorizes that macrophages, a type of immune cell, may provide a crucial link. Macrophages, literally "big eaters" in Greek, act like garbage collectors. They scavenge for debris, engulf it, and process it. In previous studies, Dr. Apte found that macrophages normally help limit the growth of new blood vessels in the eye, but with age, the cells lose this ability. The new study suggests that prior to these changes, old macrophages become less efficient at processing cholesterol.

"Ideally, macrophages should take up cholesterol, process it, and spit it out into the bloodstream. In AMD, we think the cells are ingesting cholesterol but not able to spit it out. So you get these inflamed macrophages that promote blood vessel growth," he said.

A protein called ABCA1 is needed for macrophages to release cholesterol into the bloodstream. In these experiments on mice, Dr. Apte and his team found that in old macrophages, there is a decrease in the level of ABCA1 protein. The researchers found a similar drop in ABCA1 levels in blood cells—the source of macrophages—in samples donated by older people (ages 67-87) vs. younger ones (ages 25-34). The ABCA1 gene has been identified as a risk factor for AMD (http://www.nei.nih.gov/news/pressreleases/041210.asp).

To investigate the link between these changes and blood vessel growth, the researchers first performed tests in cell culture. When grown in a dish with blood vessel cells, young macrophages efficiently stopped the cells from multiplying, but old macrophages did not. Deleting the ABCA1 gene in young macrophages caused them to behave like old macrophages. Next, the researchers tried treating old macrophages with an LXR agonist; these drugs are known to enhance cholesterol transport from macrophages by turning on the ABCA1 gene. Exposure to the drug rejuvenated the old macrophages and enabled them to inhibit blood vessel cell growth.

The researchers also tested the LXR agonist in mice with an eye injury that produces abnormal blood vessel growth, similar to that seen in neovascular AMD. Eye drops of the drug significantly reduced this blood vessel growth when given several days before the injury.

Although there is no cure for AMD, a number of treatments are available. A combination of antioxidants and zinc known as the AREDS formulation can help slow vision loss in people with intermediate (but not early) stages of AMD. There are several treatments for advanced neovascular AMD; the most common choice involves injecting the eye with drugs that block the effects of a secreted protein involved in new blood vessel formation. However, such drugs must be given frequently—up to once a month—and the repeated injections carry a risk of infection.

"If we could prevent the blood vessels from growing, it would be better than trying to eliminate them after the fact," Dr. Apte said. LXR agonists or other drugs to help macrophages clear away cholesterol might help, he said.

Having high blood cholesterol is not strongly related to AMD, and it remains to be determined whether statins and other cholesterol-modifying drugs on the market can reduce the risk of AMD. LXR agonists and other agents that modify cellular release of cholesterol are at various stages of investigation for many disorders. Some studies have found that when the drugs are given orally to mice, they appear to reduce atherosclerosis, but there have been concerns about potential toxic effects on the liver. Dr. Apte theorizes that therapy limited to the eye would not raise the same safety issues.

For more information about AMD, visit: http://www.nei.nih.gov/health/maculardegen/index.asp.

This research was supported in part by NEI grants EY016139, EY019287, and EY002687. Additional support was provided by NIH's National Heart, Lung, and Blood Institute (grants HL049373, HL094525, HL067773, HL107794, and HL30568) and National Institute of Diabetes and Digestive and Kidney Diseases (grant DK020579).

Reference: Sene A, and Khan A. et al. "Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration." Cell Metabolism, published online April 2, 2013. DOI: http://dx.doi.org/10.1016/j.cmet.2013.03.009

The National Eye Institute, part of the National Institutes of Health, leads the federal government's research on the visual system and eye diseases. NEI supports basic and clinical science programs that result in the development of sight-saving treatments. For more information, visit http://www.nei.nih.gov.

About the National Institutes of Health (NIH):

NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Daniel Stimson | EurekAlert!
Further information:
http://www.nei.nih.gov

More articles from Health and Medicine:

nachricht Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

nachricht What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>