A new study from Washington University School of Medicine in St. Louis 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 WashU Medicine researchers and their international collaborators 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 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. In macular degeneration, doctors can see cholesterol-rich deposits under the retina during an eye exam. 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, acientists were interested assessing whether reduced ApoM levels, which fall with age, could be involved in the dysfunctional cholesterol metabolism in macular degeneration and heart disease as well.
They showed that patients with macular degeneration have reduced levels of ApoM circulating in the blood compared with healthy controls. And past work by Dr. Javaheri, a WashU Medicine cardiologist, 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. Data 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 the biolipid sphingosine-1-phosphate (S1P) to get the beneficial effects of ApoM treatment in the mice.
In mice with impaired retinal cholesterol efflux, ApoM improved retinal pigment epithelium function and lipotoxicity dependentyl fro a direct interaction between S1P and S1P receptor 3 (S1P-R3). Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. The findings also could have implications for future interventions that raise ApoM in patients with heart failure.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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