The APOE4 Risk Gene's Mechanism of Glaucoma Protection Unravelled

The APOE4 Risk Gene's Mechanism of Glaucoma Protection Unravelled ...

Researchers from Mass Eye and Ear and Brigham and Women's Hospital, which are affiliated with Mass General Brigham, have identified the possible role that the apolipoprotein E4 genetic variation that is linked to Alzheimer's disease and protects against glaucoma and suggested how pharmaceutical compounds might be utilized to treat the condition.

The researchers demonstrated that theAPOE4gene variation blocks a disease cascade that results in the death of retinal ganglion cells (RGCs) in glaucoma. Moreover, they demonstrated that drug compounds can inhibit a chemical called Galectin-3, which is regulated by theAPOEgene.

Milica Margeta, PhD, a glaucoma specialist and researcher at Mass Eye and Ear, and assistant professor of ophthalmology at Harvard Medical School, claims that her research provides a better understanding of the genetic pathway that leads to irreversible blindness in glaucoma and, more importantly, suggests a therapeutic strategy to address the root cause of the vision loss.

Margeta is the lead senior author of the teams published paper in Immunity, which is titled, Apolipoprotein E4 impairs neurodegenerative retinal microglia and prevents neuronal loss in glaucoma, in which researchers concluded, These findings demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

Glaucoma is caused by the gradual loss of retinal ganglion cells, which eventually results in vision loss. Despite current medications, treatments, laser treatments, and surgeries, the disease often progresses and can result in complete blindness. Despite repeated medical and surgical interventions, the disease often progresses, and there are no clinically approved therapies that directly promote RGC survival.

Researchers have suspected that glaucoma is the result of a microscopic inflammation in the eyes. This inflammatory reaction occurs in the optic nerve of glaucoma patients, as indicated by the presence of activated microglia, which are cells that respond as first-line immune responders in the eye and brain. However, microglia can produce toxic compounds, destroy living neurons, and make neighboring cells inflammatory.

A2017 research led by research principal investigator, Oleg Butovsky, PhD, at the Brigham and Womens Hospital, explained that in Alzheimers, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglia switches from a homeostatic to a microglial neurodegenerative phenotype (MGnD), also known as disease-associated microglia (DAM). This change is controlled by apolipoprotein E (APOE).

The APOE4 variant of this gene is well-known for an increased risk of late-onset Alzheimer's disease, and, curiously, an earlier study led by MargetafoundAPOE4was associated with a decreased risk of developing glaucoma. However, the reason for the same allele being harmful in AD but protective in eye neurodegenerative diseases remains unexplored.

The researchers used RNA sequencing to examine how genes were switched on and off 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 a molecule called Galectin-3.

The researchers concluded that despite the expected increased eye pressure, microglia were unable to turn on this toxic cascade and did not produce Galectin-3, rather they remained in a homeostatic state without transitioning to a neurodegenerative phenotype in glaucoma. RGCs in APOE4 animals did not degenerate despite an increased IOP, according to the team.

The same findings were observed in mice withoutAPOE. In these animals, the toxic signaling cascade was not turned on, Galectin-3 was not produced, and neurons were protected. Moreover, these findings suggest that there are significant differences between glaucoma and AD in terms of theunderlying disease mechanisms, which may result in different outcomes of MGnD microglial activation.

Galectin-3 was significantly increased in the retina of glaucoma patients with the commonAPOE3variant, but it was almost undetectable in patients with theAPOE4variant. Therefore, myeloid cells remain more homeostatic in humans, which might explain the protective effect of this allele in human glaucoma.

Butovsky, a senior research author at Harvard Medical School, described a pharmacologic strategy that might block Galectin-3, which might be effective in treating glaucoma. These inhibitors are currently in clinical trials for the lung disease pulmonary fibrosis, which causes elevated eye pressure, and protected the retinal ganglion cells.

Our findings, demonstrating that APOE4 impairs the response of neurodegenerative microglia, have significant mechanistic and therapeutic implications for other CNS neurodegenerations, including AD.

The research explains why APOE4 is linked to a decreased risk of glaucoma, and suggests that the APOE signaling pathway is a promising target for neuroprotective therapies for this blinding disease. However, the same allele is deleterious in Alzheimers disease but protective in eye neurodegenerative diseases has yet to be addressed.

The research is claimed to be the first to investigate the role of Galectin-3 in the development of glaucoma and demonstrate the value of inhibiting this enzyme in order to avoid retinal ganglion cell death. Future research by the research team will look more closely at Galectin-3 inhibitors as therapies for glaucoma, testing them in additional animal models, as well as looking at more minimally invasive approaches of inhibitor administration, such as oral administration or in a slow-release gel.

To better understand the patient population in which Galectin-3 inhibition might be a potential therapeutic approach, ongoing studies are also looking at eye fluid and serum samples collected during glaucoma surgery. Such studies might pave the path to translating this knowledge into human clinical trials, according to the authors.

The Butovsky laboratory is also conducting work on the APOE microglial cascade and the role of the APOE4variant in microglial regulation in Alzheimers disease.

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