Fixing cholesterol metabolism problem to prevent blindness

A new study identifies a possible way to slow or block progression of age-related macular degeneration, a leading cause of blindness in people over age 50. The researchers implicated problems with cholesterol metabolism in this type of vision loss, perhaps helping to explain the links between macular degeneration and cardiovascular disease, which both worsen with age.

The new findings — identified using 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 in cholesterol processing that lead to cellular damage in the eyes and other organs. Various methods of dialing up ApoM could serve as new treatment strategies for age-related macular degeneration and perhaps some forms of heart failure triggered by similar dysfunctional cholesterol processing.

The study appears in the journal Nature Communications.

“Our study points to a possible way to address a major unmet clinical need,” said the senior author. “Current therapies that reduce the chance of further vision loss are limited to only the most advanced stages of macular degeneration and do not reverse the disease. Our findings suggest that developing treatments that increase ApoM levels could treat or even prevent the disease and therefore preserve people’s vision as they age.”

In macular degeneration, doctors can see cholesterol-rich deposits under the retina during an eye exam, according to the author. In early stages, vision might still be normal, but the deposits increase inflammation and other damaging processes the lead to the gradual loss of central vision. In the most common type, “dry” macular degeneration, the cells in the central part of the retina can be damaged, causing a type of neurodegeneration called geographic atrophy, which is similar to what happens in the brain in conditions such as Alzheimer’s disease. Dry macular degeneration can turn into “wet” macular degeneration, in which abnormal blood vessel growth damages vision.

Geographic atrophy and wet macular degeneration are advanced forms of the disease that are accompanied by vision loss. Although some approved therapies for advanced disease are available, the disease process itself is not reversible at that stage.

In recent years, evidence has emerged that ApoM can serve as a protective molecule with known anti-inflammatory effects and roles in maintaining healthy cholesterol metabolism. With that in mind, the researchers were interested assessing whether reduced ApoM levels, which fall with age, could be involved in the dysfunctional cholesterol metabolism that is at the root of multiple diseases of aging, including macular degeneration and heart disease. They showed that patients with macular degeneration have reduced levels of ApoM circulating in the blood compared with healthy controls. The authors showed that patients with various forms of heart failure also had reduced levels of ApoM in the blood.

This study revealed that ApoM is a key component in the “good cholesterol” pathways that mop up excess cholesterol — the bad kind that tends to drive inflammation — and clear it from the body through the liver.

The research suggests that when ApoM is low, cells in the retina and heart muscle can’t correctly metabolize cholesterol deposits and have a hard time getting rid of these accumulating lipids. When these lipids build up, it leads to inflammation and cellular damage.

To see if they could reverse the harmful effects of low ApoM, the researchers increased ApoM levels in mouse models of macular degeneration, using genetic modification or plasma transfer from other mice. The mice showed evidence of improved retinal health, improved function of light-sensing cells in the retina and reduced accumulation of cholesterol deposits. The researchers further found evidence that ApoM triggers a signaling pathway that breaks down the cholesterol in cellular compartments called lysosomes, which are known for playing important roles in disposing of cellular waste.

The researchers also found that ApoM must be bound to a molecule called sphingosine-1-phosphate (S1P) to get the beneficial effects of ApoM treatment in the mice.

The findings also could have implications for future interventions that raise ApoM in patients with heart failure.

“One of the exciting things about this collaboration is realizing the links between retinal pigment epithelial cells and heart muscle cell, which are both vulnerable to low ApoM,” the author said. “It is possible that the interaction between ApoM and S1P is regulating cholesterol metabolism in both cell types. We look forward to exploring strategies to increase ApoM in ways that could help the eye and the heart maintain healthy cholesterol metabolism over time and stave off two major diseases of aging.”

https://www.nature.com/articles/s41467-025-60830-1

https://sciencemission.com/Apolipoprotein-M-attenuates-age-related-macular-degeneration