Macular degeneration is the leading cause of blindness in older Americans. Much-needed prevention and treatment strategies for this pervasive disease may soon be on the way, thanks to findings published by Cell Press on April 2nd in the journal Cell Metabolism. The study sheds light on how cholesterol metabolism in white blood cells--called macrophages--contributes to this debilitating disorder and proposes new drugs, some administered via eye drops, to cure macular degeneration in mice.
"Our increased understanding of cholesterol's role in the growth of ocular blood vessels helped us identify therapeutically modifiable pathways, opening up avenues for new treatments that may help us prevent blindness caused by macular degeneration," says senior study author Rajendra Apte of Washington University School of Medicine.
In age-related macular degeneration (AMD), the growth of new blood vessels causes bleeding, scarring, and eventually cell death, slowly destroying the central part of the eye responsible for fine-detail vision. Past studies have shown that macrophage cholesterol accumulation is a common feature in AMD. In addition, macrophages promote the abnormal growth of blood vessels in the aged eye, leading to blindness. But until now, the precise mechanisms by which macrophages cause the growth of new blood vessels and potentially blindness, as well as the possible role of cholesterol metabolism in this process, were not known.
In the new study, Apte and his team found that macrophages taken from both old mice and human AMD patients had low levels of ABCA1, a cholesterol transporter known to move cholesterol out of the cells. As a result, these old macrophages accumulated high levels of cholesterol and were unable to inhibit the growth of new blood vessels. In order to restore cholesterol transport, the researchers focused on two key cholesterol regulators: Liver X Receptor (LXR), whose activation is known to promote cholesterol efflux, and microRNAs-33, which has been shown to directly decrease ABCA1 expression. Old mice were treated with either an LXR agonist, delivered via eye drops or injection, or a microRNA-33 inhibitor. Both of these drugs increased ABCA1 protein levels and improved cholesterol transport in macrophages, resulting in a reduction in the growth of blood vessels. Because the LXR agonist can be delivered with eye drops, it could potentially cause fewer side effects.
"Abnormal blood vessel growth is a characteristic of not only AMD, but also diverse disease processes outside the eye, including cancers and atherosclerosis, which are both associated with significant morbidity and mortality," Apte says. "Our findings may have significant relevance in our understanding of the pathobiology of these conditions."
Cell Metabolism, Sene et al.: "Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration."