Gene associated with high risk of Alzheimer disease may protect against glaucoma

This discovery provides potential for treatment strategy to prevent blindness from glaucoma.

Researchers from Massachusetts Eye & Ear and Brigham and Women’s Hospital, Boston, have linked the apolipoprotein E4 (APOE4) Alzheimer gene to a protective effect against glaucoma. This link, in turn, may result in a treatment strategy to prevent the devastating visual effects of glaucoma, according to lead study author Milica Margeta, MD, PhD, from the Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, and Mass Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston.

In a murine study published today in Immunity,1 the research team reported that the APOE4 gene variant exerts this dual effect of increasing the risk for Alzheimer disease but decreasing the risk of glaucoma in humans, and blocks a disease cascade that leads to the destruction of retinal ganglion cells (RGCs) in mice with glaucoma. However, the mechanism of this was unclear.

They then showed that RGC death can be prevented by medications that inhibit production of Galectin-3, which the APOE gene regulates.

In a press release, the researchers explained that considering the study findings, the APOE gene is critical in glaucoma and that inhibiting Galectin-3 may be a key to new glaucoma treatments.

Mouse models and the disease cascade

Using RNA sequencing, Dr. Margeta and colleagues investigated which genes were turned on and off in the microglia in 2 mouse models with glaucoma. The suspicion has been that inflammation occurs in the optic nerve in glaucoma, which is indicated by activated microglia, the “first-line” immune responders in the eye and brain. In the eye and in Alzheimer disease, microglia produce toxic molecules, they explained.

They found that APOE controls the microglial transition from a healthy cell to a toxic neurodegenerative cell by regulating Galectin-3.

An attempt to produce glaucoma in mice with the APOE4 variant was unsuccessful, that is, the ocular pressure was elevated but the microglia could not activate the toxic cascade and produce Galectin-3 “Instead,” they reported, “the microglia remained in a homeostatic state with preservation of the RGCs.”

The exact scenario was seen in the mice without APOE.

When Galectin-3 inhibitors were injected into the eye, the medications blocked the disease cascade in mice with glaucoma, and the RGCs were protected despite the elevated eye pressure. The scientists also analyzed human eye tissue, and they confirmed the elevated levels of Galectin-3 in the retina of glaucoma patients with the common APOE3 variant, but Galectin-3 almost undetectable in patients with the APOE4 variant. 

According to the investigators, this study is the first to examine the role of Galectin-3 in the development of glaucoma and to show the value of inhibiting this molecule in order to prevent RGC death.

The next step will be to analyze Galectin-3 inhibitors with the goal of testing them in clinical trials. Oral administration or application of a slow-release gel may be future delivery routes.

Reference
1. Margeta M, Yin Z, Madore C, et al. Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma. Immunity. Published online August 15, 2022; https://doi.org/10.1016/j.immuni.2022.07.014