New research led by scientists at Mass Eye and Ear and Brigham and Women’s Hospital, member hospitals of Mass General Brigham, reveals the role that a genetic variant associated with Alzheimer’s disease, APOE4, plays in protecting against glaucoma. In the new study, published August 16 in Immunity, the researchers also used a pharmacologic treatment to successfully prevent the destruction of neurons in the eyes of mice with glaucoma by targeting the APOE signaling pathway.
Specifically, the scientists demonstrated that the APOE4 gene variant, which increases risk for Alzheimer’s but decreases risk of glaucoma in humans, blocks a disease cascade that leads to the destruction of retinal ganglion cells in glaucoma. Additionally, they showed in separate mouse models that the death of retinal ganglion cells — the cause of vision loss in glaucoma — can be prevented by using medications to inhibit a molecule called Galectin-3, which is regulated by the APOE gene. These findings taken together emphasize the critical role of APOE in glaucoma and suggest that Galectin-3 inhibitors hold promise as a glaucoma treatment, according to the authors.
“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 lead study author Milica Margeta, MD, PhD, a glaucoma specialist and scientist at Mass Eye and Ear, and assistant professor of ophthalmology at Harvard Medical School. “This study shows that the APOE-mediated disease cascade is clearly harmful in glaucoma, and that when you interfere with it genetically or pharmacologically, you can actually stop the disease.”
Understanding and halting the cause of vision loss in glaucoma
Glaucoma is a leading cause of blindness, affecting an estimated 80 million people worldwide. Despite how common the disease is, little is known about the underlying mechanisms that lead to the loss of retinal ganglion cells, which ultimately results in vision loss. Accordingly, there is no treatment to directly promote survival of these cells; current treatments, including medications, laser therapies and surgeries are aimed at lowering eye pressure, the only modifiable risk factor for glaucoma. However, the disease often progresses despite these interventions and can result in complete blindness.
Scientists have suspected that glaucoma may be the result of a microscopic inflammatory process in the eyes. Previous studies by this research team and others, showed that this inflammatory process occurs in the optic nerve of glaucoma patients, as indicated by the presence of activated microglia, which are cells that act as first-line immune responders in the eye and brain. Microglia can be beneficial in healthy tissue; however, in eye diseases and neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, microglia can produce toxic molecules, destroy living neurons, and make neighboring cells become inflammatory.
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