National Glaucoma Research - Current Award

	Ian Trounce, Ph.D. Centre for Eye Research Australia, The University of Melbourne Melbourne, Australia Title: The Effect Of Glaucoma Risk Factors On APP Processing In Retinal Ganglion Cells Non-Technical Title: Alzheimer’s Disease Proteins In Glaucoma Acknowledgements: Recipient of the Thomas R. Lee award for National Glaucoma Research Duration: April 1, 2009 - March 31, 2011 Award Type: Standard Award Amount: $94,834
Summary: 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.

Details:

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 study aims to look at the influence of high eye pressure and increasing age, the two major risk factors for glaucoma, on APP breakdown. These experiments will shed light on whether age-related changes in APP processing account for the vulnerability of older eyes to glaucoma. If this is the case, then further work aimed at restoring APP and preventing amyloid beta will likely prove fruitful in developing new treatments for 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 two year grant, we are exploring the hypothesis that the protein called amyloid precursor protein (APP) that is linked to Alzheimer's disease loses its protective function in the eye due to the glaucoma risk factors of increasing age and increased pressure within the eye. We are using a mouse model of human glaucoma. In the first year, we have established that the APP protein does appear to be more quickly degraded as a consequence of a short period of increased eye pressure, and that the degraded protein fragments differ from those seen in brain. This is new information that suggests that different enzyme proteins may act on the APP found in the retina as compared with APP found in the brain. A further novel finding in our work supported by AHAF is the discovery of the molecular pathway that the APP protein “amplifies” to protect cells from certain poisons.

Work to be completed in the second year of the grant will examine whether a longer-term increase in eye pressure further degrades the APP protein to prevent it from protecting nerves in the eye, and whether adding this protein directly to the eye can protect it from pressure injury.

In summary, we are excited that our early results support our hypothesis that APP may be important in eye health. Also, our new and surprising findings may, with further research, identify new ways of preventing the loss of nerve cells in glaucoma that ultimately result in loss of vision.