The Effect of Glaucoma Risk Factors on APP Processing in Retinal Ganglion Cells

This study aims to study the influence of high eye pressure and increasing age, the two major risk factors for glaucoma, on how the “Alzheimer’s disease” protein “amyloid precursor protein” (APP) breaks down. These experiments will shed light on whether age-related changes in the way this protein functions account for the vulnerability of older eyes to glaucoma. If this is the case, then further work aimed at restoring APP will likely prove fruitful in developing new treatments for glaucoma.

Glaucoma and Alzheimer’s disease are potentially debilitating degenerative diseases of the nervous system resulting in blindness and memory loss respectively. The frequency of both diseases increases dramatically as people age. The reason for this is not known, but if we can determine what makes nerves in older individuals vulnerable to these diseases, we may be able to identify robust treatments that protect nerves and prevent these diseases from progressing.

Recent evidence indicates that there may be similarities in the biological processes that result in nerve cell loss in both of these diseases. The breakdown of a protein, amyloid precursor protein, or APP, to a toxic by product (amyloid beta) is thought to contribute to memory loss in Alzheimer’s disease. Recent evidence indicates that this abnormal processing of APP may also occur in the retina in glaucoma raising the intriguing possibility that similar processes are responsible for both diseases. This would potentially have a major impact on glaucoma as it would provide a whole host of potential treatments that might protect the optic nerve and prevent vision loss in glaucoma.

This project brings together Prof. Jonathan Crowston, a clinician-scientist with expertise in glaucoma, and Dr. Ian Trounce, a neuroscientist with expertise in Alzheimer’s disease and APP. They have recognized a strong overlap of interests, and believe that combining their knowledge puts them in a strong position to address the following aims:

1. To determine whether elevated eye pressure alters APP breakdown in optic nerve cells in the mouse.
2. To determine whether increasing age alters APP breakdown in the optic nerve and whether aging makes the optic nerve more vulnerable to elevated eye pressure.
3. To determine whether restoration of APP can reverse the effect of aging and protect the optic nerve from damage.

Progress Updates

In this project, Drs. Ian Trounce, Jonathan Crowston and colleagues determined that the Alzheimer’s disease protein, called amyloid precursor protein (APP), may lose its protective function in the eye due to the glaucoma risk factors of increased age and increased eye pressure. These researchers have established the pathway that the APP protein triggers to protect nerve cells. In addition, they discovered that APP is abundant in the vitreous (the whitish gel that gives the eyeball its shape), which suggests it has an important role protecting the eye nerve cells that are lost to glaucoma. They also found that the protein decreases in abundance in the aging human eye. In the future, they will determine whether adding APP to the eye protects it from pressure-induced eye injury. These findings may provoke great interest from the wider brain disease research community due to the possible overlap of glaucoma and Alzheimer’s disease. Drs. Trounce and Crowston believe that drugs based on this new nerve protection pathway may be developed to prevent nerve cell loss in both of these diseases.