Alzheimer's is a progressive neurodegenerative disorder characterised by the formation of senile plaques consisting of amyloid-beta protein. The molecular genetic basis of Alzheimer's is very complex. Amyloid-beta is a toxic protein fragment produced by abnormal processing of amyloid precursor protein (APP), which accumulates to form the insoluble plaques found within cells. (This occurs by a seeding mechanism similar to that of prion proteins.)
A new study, by researchers at UCL's Institute of Ophthalmology, in collaboration with French and Italian colleagues, now confirms the role of amyloid-beta in the eye disease glaucoma, in which retinal cells degenerate. They report that amyloid-beta deposits form by the same mechanism as in Alzheimer's, and that preventing their formation significantly reduces cell death in the glaucomatous retina. The findings open up a new avenue for the development of new glaucoma treatments.
Like Alzheimer's, glaucoma is a progressive degenerative disorder. It is characterized by the death of retinal ganglion cells (RGCs), whose cell fibres form the optic nerve which carries visual information from the eye to the brain. This cell death then leads to optic nerve damage.
Death of RGCs is associated with increased pressure within the eye, and all current glaucoma treatments are based on lowering this pressure. However, the continued death of RGCs in glaucoma patients whose intraocular pressure has been normalized suggests that there are other mechanisms at work.
Amyloid-beta protein had already been implicated in glaucoma. It is, for example, known that RGCs degenerate in Alzheimer's patients, who suffer impaired vision as a consequence.
Guo, et al used an established animal model of glaucoma to investigate the role of amyloid-beta in RGC degeneration. They induced high intraocular pressure in rats, then analyzed the retinal tissue to determine the distribution of the protein within it.
Using antibody staining, they found that, in glaucomatous animals but not controls, amyloid-beta levels were significantly increased in the tissue layer containing the cell bodies of RGCs. On the other hand, the levels of full-length APP in the experimental animals' retinae had decreased (consistent with the knowledge that former protein is produced by degradation).
The researchers then injected various fragments of APP, including amyloid-beta, directly into the rats' eyes. Amyloid-beta induced death of RGCs, which peaked at around 72 hours after the injections. The extent of cell death was found to be dependent on the concentration of amyloid-beta injected.
They then used agents to block amyloid-beta function in various ways. First, they treated glaucomatous rats with a compound that inhibits beta-secretase, one of the enzymes involved in APP processing. Then, rats were treated with a compound that inhibits the aggregation of amyloid-beta fragments. And finally, they used an antibody to neutralize amyloid-beta.
All three treatments had a neuroprotective effect. Each reduced RGC death, and delayed the the peak of cell death from 3 to 8 weeks after experimental intraocular pressure was induced. When each treatment was given alone, the amyloid-beta antibody was found to be the most effective treatment. But cell death was reduced most when the treatments were used in combination.
As well as confirming the role of amyloid-beta protein in glaucoma, these findings suggest that the condition could be treated by targetting amyloid-beta in the eye using a combination of protective agents administered during the period when intraocular pressure is increasing.
Guo, L., et al. (2007). Targeting amyloid-beta in glaucoma treatment. PNAS doi: 10.1073/pnas.0703707104. [Full text]