Alzheimer's-linked gene could be key to stymying glaucoma

Apolipoprotein E (Apoe) has not just now hit scientists' radar. The gene is a major player in the brain and has been associated with Alzheimer’s disease given its ability to switch the role of microglia from a homeostatic role to neurodegenerative. 

But scientists from Mass General Brigham have uncovered a potential new impact of the gene—particularly the Apoe4 variant—in glaucoma. Unlike in Alzheimer’s, where Apoe4 is a risk factor for late-onset disease, the gene is believed to be protective against glaucoma, which is the leading cause of blindness.

“Our research provides greater understanding of the genetic pathway that leads to irreversible blindness in glaucoma, and importantly, points to a possible treatment to address the root cause of the vision loss,” said Milica Margeta, M.D., Ph.D., in a press release.

Margeta is an eye specialist at Mass Eye and Ear and lead author of the paper published in Immunity. Her prior research uncovered that Apoe4 reduced the risk of glaucoma.

And now, scientists have a better understanding of why. To dive into how Apoe4 reduces glaucoma risk, the scientists used a glaucoma mouse model to interrogate the actions of Apoe and its mutated counterpart Apoe4, specifically mice without the Apoe gene and mice with the Apoe4 gene variant.

Using RNA sequencing, the scientists found that Apoe operated the control panel, pulling biological levers that resulted in microgials turning from beneficial to harmful. One of those levers is regulating Galectin-3, a molecule that contributes to microglial function going awry. 

But when Apoe was shut off, Galectin-3 wasn’t produced, and retinal cells were maintained. The same happened when mice had the Apoe4 allele. The findings could form the basis for future glaucoma therapies. 

“This was a striking finding and led to testing whether a pharmacologic intervention could block Galectin-3, which could potentially treat glaucoma,” study co-author Oleg Butovsky, Ph.D., said in the release. Galectin-3 inhibitors are not new but have for the most part been directed at treating an assortment of lung diseases including non-small cell lung cancer and lung fibrosis. One such therapy is being developed by Galecto Biotech for lung cancer combined with Roche’s Tecentriq. 

When used in mice with glaucoma, the disease cascade that results in the death of retinal cells was blocked. As a result, the team is going to further investigate Galectin-3 inhibitors to treat glaucoma and the delivery method of potential therapies. The scientists also say they’re going to study eye fluids in patients who have glaucoma surgery to see whether elevated Galectin-3 levels would be a suitable biomarker for crafting an ideal patient population.