Gene associated with Alzheimer’s risk may promise treatment strategy to prevent vision loss

New research by scientists from Harvard Medical School of Massachusetts Eye and Ear and Brigham and Women’s Hospital reveals the role that a genetic variant associated with Alzheimer’s disease, APOE4, plays in protecting against glaucoma.

  • By RYAN JASLOW | mass eye and ear

In the new study, published Aug. 16 in Immunity, researchers also used a pharmacological treatment to successfully prevent the destruction of neurons in the eyes of mice with glaucoma by targeting the APOE (apolipoprotein E) signaling pathway.

Specifically, the scientists demonstrated that the APOE4 gene variant, which increases the risk of Alzheimer’s disease but decreases the risk of glaucoma in humans, blocks a disease cascade that leads to the destruction of retinal ganglion cells in the glaucoma. What’s more, they showed in separate mouse models that retinal ganglion cell death – the cause of vision loss in glaucoma – can be prevented by using drugs to inhibit a molecule called Galectin-3, which is regulated by the APOE gene.

These results taken together underscore the critical role of APOE in glaucoma and suggest that galectin-3 inhibitors hold promise as a treatment for glaucoma, according to the authors.

“Our research provides a better 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 vision loss,” said the study’s lead author. , Milica Margeta, Assistant Professor of Ophthalmology and HMS. glaucoma specialist and scientist at Mass Eye and Ear. “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, stopping the cause of vision loss in glaucoma

Glaucoma is one of the leading causes of blindness, affecting approximately 80 million people worldwide. Despite the frequency of the disease, little is known about the underlying mechanisms that lead to the loss of retinal ganglion cells, which ultimately leads to loss of vision. Consequently, there is no treatment to directly promote the survival of these cells; current treatments, including drugs, laser therapies, and surgeries, aim to reduce eye pressure, the only modifiable risk factor for glaucoma. However, the disease often progresses despite these interventions and can lead to complete blindness.

Scientists suspect that glaucoma may be the result of a microscopic inflammatory process in the eyes. Previous studies by this research team and others have shown that this inflammatory process occurs in the optic nerve of glaucoma patients, as indicated by the presence of activated microglia, cells that act as immune responders to first line in the eye and the brain. Microglia can be beneficial in healthy tissue; however, in eye diseases and neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, microglia can produce toxic molecules, destroy living neurons, and make nearby cells inflammatory.

A 2017 seminal study led by lead researcher Oleg Butovsky, associate professor of neurology at HMS at Brigham and Women’s, found that in neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and sclerosis in plaques, microglia transition to a microglial neurodegenerative (MGnD) phenotype, mediated by the APOE gene. It is well established in neurological research that a variant of this gene, APOE4, is linked to an increased risk of late-onset Alzheimer’s disease. Interestingly, an earlier study led by Margeta found that APOE4 is associated with a decreased risk of developing glaucoma, but it was unclear why.

The new study by Margeta and Butovsky sheds light on this mechanism. The scientists used RNA sequencing to provide unbiased insight into turned on and off genes in microglia in different mouse models with glaucoma. They identified a disease cascade in which APOE controls the microglial transition from a healthy cell to a toxic neurodegenerative cell by regulating another molecule called galectin-3.

When researchers attempted to induce glaucoma in mice with the APOE4 variant, they found that, despite the expected elevated eye pressure, microglia were unable to activate this toxic cascade and did not produce galectin-3, remaining rather in a homeostatic state with preservation of retinal ganglion cells. The same results were observed in mice without APOE: the toxic signaling cascade was not activated, galectin-3 was not produced and neurons were protected. Scientists also analyzed human eye tissue samples provided by Duke University Medical Center and confirmed that galectin-3 was increased in the retinas of glaucoma patients with the common APOE3 variant, but was almost undetectable in patients with the APOE4 variant.

“This was a striking finding and led to testing whether a pharmacological intervention could block galectin-3, which could potentially treat glaucoma,” explained the study’s lead author, Butovsky.

The scientists used galactin-3 inhibitors, which can be derived from natural sources and are currently in clinical trials for pulmonary fibrosis, a lung disease. They found that injecting these inhibitors into the eye blocked the disease cascade in mice with glaucoma and that retinal ganglion cells were protected despite elevated eye pressure.

“Our results explain why APOE4 is associated with a reduced risk of glaucoma and show that the APOE signaling pathway is a promising target for neuroprotective treatments for this blinding disease. However, why the same allele is deleterious in Alzheimer’s disease but protective in ocular neurodegenerative diseases has not yet been addressed,” Butovsky said.

Paving the way for clinical trials

This study is the first to examine the role of Galectin-3 in the development of glaucoma and to show the interest of inhibiting this molecule to prevent the death of retinal ganglion cells.

Future studies by this research team will take a closer look at galectin-3 inhibitors as treatments for glaucoma, testing them in other animal models and examining more minimally invasive approaches to inhibitor delivery. , such as oral administration or in a slow-release gel. .

Ongoing studies are also examining ocular fluid and serum samples collected from patients during glaucoma surgery to better understand the patient population in which galectin-3 inhibition would be a potential therapeutic approach. For example, patients might be candidates for treatment with inhibitory drugs if galectin-3 is found to be elevated in their biofluids. Such studies can pave the way for translating this research into human clinical trials, according to the authors.

“Glaucoma remains a blinding disease for millions of people around the world, and these exciting findings from Drs Margeta and Butovsky and their team provide insight into the role of genetic variants and the promise of translation into a treatment for patients,” said Joan Miller, the David Glendenning Cogan Professor of Ophthalmology and Chairman of Ophthalmology at HMS and Chief of Ophthalmology at Mass Eye and Ear, Massachusetts General Hospital and Brigham and Women’s.

Butovsky and his lab are researching the APOE microglial cascade and the role of the APOE4 variant in the microglial regulation of Alzheimer’s disease.

Study co-authors included Zhuoran Yin, Charlotte Madore, Kristen M. Pitts, Sophia M. Letcher, Jing Tang, Shuhong Jiang, Christian D. Gauthier, Sebastian R. Silveira, Caitlin M. Schroeder, Eleonora M. Lad , Alan D. Proia, Rudolph E. Tanzi, David M. Holtzman, Susanne Krasemann, and Dong Feng Chen.

This study was funded by the Cure Alzheimer’s Fund, National Eye Institute, National Institute of Neurological Disorders and Stroke, BrightFocus Foundation, American Glaucoma Society Young Clinician Scientist Award, and Research to Prevent Blindness Career Development Award.

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