A new study from Washington University School of Medicine in St. Louis has revealed a possible way to slow or stop the progression of age-related macular degeneration, one of the leading causes of blindness in people over 50. The WashU Medicine researchers and their international collaborators have identified problems with cholesterol metabolism as a cause of this type of vision loss. This could potentially explain a link between macular degeneration and cardiovascular disease, both of which worsen with age.
The new findings, based on human plasma samples and mouse models of macular degeneration, suggest that increasing the amount of a molecule called apolipoprotein M (ApoM) in the blood fixes problems with cholesterol processing that lead to cell damage in the eyes and other organs. Different methods of increasing ApoM levels could serve as new treatment strategies for age-related macular degeneration and possibly some forms of heart failure caused by a similar cholesterol processing disorder.
Macular Degeneration and Vision Loss
“Our study points to a potential way to address a major unmet clinical need,” said lead author Rajendra S. Apte, MD, PhD, Paul A. Cibis Distinguished Professor of Ophthalmology and Vision Sciences at WashU Medicine. “Current therapies that reduce the risk of further vision loss are limited to the most advanced stages of macular degeneration and cannot reverse the disease. Our findings suggest that developing treatments that increase ApoM levels could treat or even prevent the disease and thus preserve vision in older people.”
In macular degeneration, doctors can detect cholesterol-rich deposits under the retina during an eye examination, according to Apte. In early stages, vision may still be normal, but the deposits increase inflammation and other damaging processes that lead to a gradual loss of central vision. In the most common form, “dry” macular degeneration, the cells in the central part of the retina can become damaged, leading to a type of neurodegeneration called geographic atrophy, which is similar to what happens in the brain in diseases such as Alzheimer’s disease. Dry macular degeneration can develop into “wet” macular degeneration, where abnormal blood vessel growth damages vision. Geographic atrophy and wet macular degeneration are advanced forms of the disease that are associated with vision loss. Although some approved therapies are available for advanced disease, the disease process itself is not reversible at this stage.
Low levels of ApoM Increase the Risk of Eye Disease and Heart Failure
In recent years, evidence has accumulated that ApoM may serve as a protective molecule with known anti-inflammatory effects and functions in maintaining healthy cholesterol metabolism. With this in mind, Apte and co-senior author Ali Javaheri, MD, PhD, assistant professor of medicine, set out to investigate whether declining ApoM levels with age could be involved in the disruption of cholesterol metabolism that underlies various diseases of aging, such as macular degeneration and heart disease. They showed that patients with macular degeneration have reduced levels of ApoM in their blood compared to healthy controls. Earlier work by Javaheri, a cardiologist at WashU Medicine, showed that patients with various forms of heart failure also have reduced levels of ApoM in their blood.
This study has shown that ApoM is a key component in the “good cholesterol” metabolic pathways that break down excess cholesterol – the bad cholesterol that promotes inflammation – and eliminate it from the body via the liver. Research suggests that when ApoM levels are low, cells in the retina and heart muscle cannot properly metabolize cholesterol deposits and have difficulty breaking down these accumulated lipids. When these lipids accumulate, inflammation and cell damage occur. To see if they could reverse the harmful effects of low ApoM levels, the researchers increased ApoM levels in mouse models with macular degeneration using genetic modification or plasma transfer from other mice. The mice showed signs of improved retinal health, improved function of light-sensitive cells in the retina and reduced accumulation of cholesterol deposits.
Ensuring Healthy Cholesterol Metabolism in the Eyes and Heart
The researchers also found evidence that ApoM triggers a signaling pathway that breaks down cholesterol in cellular compartments called lysosomes, which are known for their important role in the disposal of cellular waste. They also found that ApoM must be bound to a molecule called sphingosine-1-phosphate (S1P) to achieve the beneficial effects of ApoM treatment in mice. The findings could also have implications for future interventions that increase ApoM levels in patients with heart failure. “One of the exciting aspects of this collaboration is the finding that there is a link between retinal pigment epithelial cells and cardiac muscle cells, both of which are sensitive to low ApoM levels,” said Javeheri. It is possible that the interaction between ApoM and S1P regulates cholesterol metabolism in both cell types. The researchers would like to find strategies to increase ApoM in order to keep cholesterol metabolism in the eyes and heart at a healthy level in the long term and thus prevent two serious age-related diseases.