Summary: A new study indicates that raising levels of apolipoprotein M (ApoM) may slow or prevent progression of age-related macular degeneration (AMD), a leading cause of vision loss in older adults. Researchers found that low ApoM disrupts cholesterol metabolism in the retina, promoting inflammation and cellular damage that contribute to vision decline, particularly in advanced forms such as geographic atrophy.
In mouse models, increasing ApoM improved retinal health and reduced cholesterol accumulation by engaging a protective sphingosine-1-phosphate (S1P) signaling pathway. These results point to a potential therapeutic approach that could preserve vision and also offer benefits for heart failure, a condition that shares similar defects in cholesterol handling.
Key Facts:
- ApoM Deficiency: Lower ApoM impairs cholesterol metabolism in the eye and heart, leading to inflammation and tissue injury.
- Therapeutic Potential: Increasing ApoM levels restored retinal function and reduced lipid deposits in mouse models of AMD.
- Dual Benefit: Targeting ApoM and its partner sphingosine-1-phosphate may help both macular degeneration and certain forms of heart failure.
Source: WUSTL
A new study from Washington University School of Medicine in St. Louis identifies a promising strategy to slow or block age-related macular degeneration (AMD), a top cause of blindness in people over 50.
Researchers at WashU Medicine and international collaborators traced part of AMD’s progression to disrupted cholesterol metabolism in the retina, a link that may help explain the association between macular degeneration and cardiovascular disease, both of which elevate in incidence with age.
Using human plasma samples and mouse models of AMD, the team found that increasing the level of apolipoprotein M (ApoM) in the bloodstream corrected defects in cholesterol processing that otherwise lead to cellular injury in the eye and other organs. Multiple approaches to raise ApoM may therefore represent new treatment strategies for age-related macular degeneration and possibly for forms of heart failure driven by similar lipid-processing dysfunction.
The study was published June 24 in the journal Nature Communications.
“Our study points to a possible way to address a major unmet clinical need,” said senior author Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences at WashU Medicine. “Current therapies that reduce the risk of further vision loss apply only at the most advanced stages and do not reverse the disease. Developing treatments that increase ApoM could treat—or even prevent—AMD and help preserve vision as people age.”
Clinicians can observe cholesterol-rich deposits under the retina during eye exams in patients with macular degeneration. Early in the disease, central vision may remain intact, but these deposits drive inflammation and damaging processes that eventually cause progressive central vision loss.
Dry AMD, the most common form, causes damage to retinal cells and can progress to geographic atrophy, a neurodegenerative loss of retinal tissue analogous in some ways to neurodegeneration seen in conditions like Alzheimer’s disease. Dry AMD can further advance to wet AMD, which involves abnormal blood vessel growth that harms vision. While treatments exist for certain advanced stages, the underlying disease process is not reversible at that point.
A common culprit in eye disease and heart failure
Evidence has been mounting that ApoM functions as a protective molecule with anti-inflammatory properties and an important role in healthy cholesterol metabolism. Given that ApoM declines with age, the research team—led by Apte and co-senior author Ali Javaheri, MD, PhD—investigated whether reduced ApoM could underlie the defective cholesterol handling implicated in age-related diseases such as AMD and heart failure.
The investigators found that people with AMD had significantly lower circulating ApoM than healthy controls. Earlier work by Javaheri, a cardiologist, also showed that patients with various forms of heart failure exhibit reduced ApoM levels.
The study demonstrates that ApoM contributes to “good cholesterol” pathways that clear excess, inflammation-promoting cholesterol from tissues and transport it to the liver for disposal. When ApoM is low, retinal and cardiac cells struggle to metabolize and remove accumulating lipids. The resulting lipid buildup provokes inflammation and cellular injury.
To test whether raising ApoM could reverse these harmful effects, the team increased ApoM in mouse models of AMD using genetic approaches and by transferring plasma from donor animals. Treated mice displayed better retinal health, improved function of photoreceptor-supporting cells, and less accumulation of cholesterol-rich deposits.
Mechanistic studies showed that ApoM activates a signaling pathway involving sphingosine-1-phosphate (S1P) that promotes breakdown of cholesterol inside lysosomes—cellular compartments responsible for degrading and recycling waste. Crucially, ApoM’s protective effects required binding to S1P. The authors also demonstrated that loss of lysosomal acid lipase in retinal pigment epithelial cells recreates features of AMD, supporting the role of lysosomal lipid catabolism in disease progression.
Apte and Javaheri have partnered with Mobius Scientific, a Washington University startup formed to translate these insights into therapies that raise ApoM or harness ApoM-S1P signaling to prevent or treat AMD. The research also points toward interventions that might boost ApoM in heart failure patients to correct overlapping cholesterol-processing defects.
“One exciting aspect of this work is the shared vulnerability of retinal pigment epithelial cells and heart muscle cells to low ApoM,” Javaheri said. “ApoM and S1P may regulate cholesterol metabolism in both tissues. We look forward to developing strategies to elevate ApoM that could protect the eye and the heart from major age-related diseases.”
Funding: This research was supported by the National Institutes of Health (grants R01 EY019287, P30 EY02687, 1T32GM1397740-1, K08HL138262, 1R01HL155344, P30DK020579, P30DK056341), the Jeffrey T. Fort Innovation Fund, the Starr Foundation AMD Research Fund, the Siteman Retina Research Fund, Research to Prevent Blindness, the Carl Marshall and Mildred Almen Reeves Foundation, the Retina Associates of St. Louis Research Fund, a pilot grant from the Washington University Genome Technology Access Center, the Vitreoretinal Surgery Foundation Fellowship, the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital, the Longer Life Foundation, and the Austrian Science Fund.
The content of the study is the responsibility of the authors and does not necessarily represent official NIH views. Apte and Javaheri have intellectual property licensed by Washington University to Mobius Scientific. Apte serves as chief scientific officer of Mobius Scientific and both serve on its advisory board.
About this AMD and genetics research news
Author: Abeeha Shamshad
Source: WUSTL
Contact: Abeeha Shamshad – WUSTL
Image: Image credited to Neuroscience News
Original Research (open access): “Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism” by Rajendra S. Apte et al., Nature Communications.
Abstract
Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism
Age-related macular degeneration (AMD) is a leading cause of blindness in adults over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid accumulation. Given ApoM’s role as a lipocalin that binds sphingosine-1-phosphate (S1P), the authors hypothesized that ApoM might restore lipid homeostasis and retinal function in AMD.
They report that patients with AMD have significantly lower ApoM than controls. In mouse models with impaired retinal cholesterol efflux, ApoM improved retinal pigment epithelium (RPE) function and reduced lipotoxicity through mechanisms dependent on S1P and S1P receptor 3. Ultrastructural observations revealed enhanced interactions between melanosomes and lipid droplets, which led to the discovery that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase reproduced AMD-like features. The study defines a novel role for ApoM-S1P signaling in preventing RPE lipotoxicity via lysosomal lipid degradation, offering a potential therapeutic pathway for AMD and related age-associated disorders.