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A Gene That Makes You More Likely To Get Alzheimer’s Keeps You From Going Blind

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A leading cause of blindness, glaucoma is thought to impact 80 million people globally. Even though the disease is very common, not much is known about what causes retinal ganglion cells to die, which is what causes vision loss in the end.

Since eye pressure is the only modifiable risk factor for glaucoma, there is currently no treatment to specifically encourage the survival of these cells.

Instead, present treatments, such as drugs, laser therapies, and surgeries, are focused on reducing eye pressure. But even with these treatments, the disease often gets worse and can lead to total blindness.

Now, a new study headed by doctors at Mass Eye and Ear and Brigham and Women’s Hospital, both part of Mass General Brigham, demonstrates the impact that APOE4, a genetic variant associated with Alzheimer’s disease, plays in glaucoma prevention.

In this new study, which was published in the journal Immunity used, also used a drug treatment that targeted the APOE signaling system to successfully prevent the death of neurons in the eyes of glaucomatous mice.

In particular, the researchers showed that a disease cascade that causes the degeneration of retinal ganglion cells in glaucoma is blocked by the APOE4 gene mutation, which raises the risk for Alzheimer’s disease but lowers the risk of glaucoma in humans.

Additionally, they demonstrated in various mice models that drugs that block the Galectin-3 protein, which is controlled by the APOE gene, can prevent the death of retinal ganglion cells, the source of visual loss in glaucoma. According to the authors, these findings collectively highlight the crucial function of APOE in glaucoma and imply that galectin-3 inhibitors show promise as a glaucoma treatment.

The findings of the study, according to lead author Milica Margeta, provide “greater understanding of the genetic pathway that leads to irreversible blindness in glaucoma and, importantly, point to a possible treatment to address the root cause of the vision loss.”

This study provides further evidence that the APOE-mediated disease cascade is detrimental in glaucoma and that its disruption, either genetically or pharmacologically, can halt the progression of the illness.

Understanding and stopping the source of glaucoma-related visual loss

A leading cause of blindness, glaucoma is thought to impact 80 million people globally. Even though the disease is very common, not much is known about what causes retinal ganglion cells to die, which is what causes vision loss in the end. Since eye pressure is the only modifiable risk factor for glaucoma, there is currently no treatment to specifically encourage the survival of these cells. Instead, present treatments, such as drugs, laser therapies, and surgeries, are focused on reducing eye pressure. But even with these treatments, the disease often gets worse and can lead to total blindness.

Glaucoma is a condition that has been hypothesized by scientists to be caused by a tiny inflammatory process that occurs in the eyes. The presence of activated microglia, which are cells that serve as first-line immune responders in the eye and brain, indicates that this inflammatory process happens in the optic nerves of glaucoma patients, as demonstrated by previous study by this team and others. In healthy tissue, microglia can be helpful; but, in diseases of the eyes and neurological disorders like Alzheimer’s and Parkinson’s disease, microglia can create toxic chemicals, kill active neurons, and cause inflammation in nearby cells.

In neurodegenerative diseases, such as Alzheimer’s, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglia switch to a microglial neurodegenerative phenotype (MGnD), which is mediated by the APOE (Apolipoprotein E) gene, according to a groundbreaking 2017 study led by Oleg Butovsky, PhD, of the Department of Neurology at Brigham and Women’s Hospital. A high risk for developing Alzheimer’s disease in old age has been related to a specific version of the APOE4 gene, according to numerous studies conducted in the field of neuroscience. It’s interesting to note that APOE4 has been linked to a lower chance of getting glaucoma, although the reason for this association was not clear in a prior study led by Dr. Margeta.

Drs. Margeta and Butovsky’s latest research illuminates this mechanism. The researchers used RNA sequencing to provide an unbiased look at which genes were active and inactive in microglia in various glaucoma-affected mice models. They discovered a disease cycle in which APOE regulates another molecule called Galectin-3, causing the microglia to change from a healthy cell to a toxic neurodegenerative cell.

In spite of the anticipated increased eye pressure, researchers who attempted to cause glaucoma in a mouse with the APOE4 variant discovered that the microglia were unable to activate this toxic cascade and did not produce Galectin-3, instead remaining in a homeostatic state with the preservation of retinal ganglion cells. The same results were seen in animals lacking APOE: neurons were protected, the hazardous signaling cascade was not activated, and Galectin-3 was not generated. The scientists also looked at human eye tissue samples from Duke University Medical Center and found that Galectin-3 was higher in the retinas of glaucoma patients with the common APOE3 variant but almost impossible to find in patients with the APOE4 variant.

The study’s principal author, Dr. Butovsky, who is also an associate professor of neurology at Harvard Medical School, said, “This was a striking finding and led to testing whether a pharmacologic intervention could block Galectin-3, which could potentially treat glaucoma.”

The scientists employed natural Galactin-3 inhibitors in clinical trials for pulmonary fibrosis. In mice with glaucoma, they discovered that injecting these inhibitors stopped the disease cascade, and the retinal ganglion cells were still protected despite increased eye pressure.

According to Dr. Butovsky, “our findings provide an explanation as to why APOE4 is associated with a decreased risk of glaucoma and show that the APOE signaling pathway is a promising target for neuroprotective treatments for this blinding disease. 

“However,” the author added, “why the same allele is deleterious in Alzheimer’s disease but protective in eye neurodegenerative diseases has yet to be addressed.”

Preparing for clinical trials

This work is the first to investigate Galectin-3’s role in the onset of glaucoma and to demonstrate the importance of blocking this protein to stop the loss of retinal ganglion cells.

The future study by this team will examine Galectin-3 inhibitors more closely as glaucoma treatments, testing them in new animal models and examining less invasive delivery methods of inhibitors such as oral administration or slow-release gel.

As part of ongoing research, ocular fluid and serum samples taken from glaucoma patients are being examined in order to identify the patient subset for which galectin-3 suppression might be an effective treatment. For instance, if a patient’s biofluids are found to have elevated levels of galectin-3, it may indicate that the patient may be a candidate for treatment with the inhibitor drug. According to the authors, these findings can open the path for the translation of this study into human clinical trials.

Dr. Butovsky’s lab is investigating the APOE microglial cascade and the role of the APOE4 variation in microglial regulation in Alzheimer’s disease.

Image Credit: Getty

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