Purpose  Glaucoma is an optic neuropathy caused by the chronic and progressive death of retinal ganglion cells (RGCs), resulting in irreversible blindness. Ocular hypertension is a major risk factor, but RGC death often continues after ocular hypertension is normalized, and can take place with normal tension. Continuous RGCs death was related in rodents and humans to the local upregulation of neurotoxic proteins such as TNF-α. Previously we showed in rat models of glaucoma that ocular hypertension also up-regulates expression of α2-macroglobulin, which is neurotoxic. α2-macroglobulin up-regulation in retina is long–lived even after high IOP is reduced with medication. Here we sought to examine α2-acroglobulin as a possible biomarker in human glaucoma, and to study a possible neurotoxic mechanism of action.
Methods  Quantitative western blotting of α2-macroglobulin in samples obtained from aqueous humor (human and rat) and retina (rat). Ex vivo neuronal survival assays, and NGF–α2-macroglobulin binding studies using surface plasmon resonance.
Results  We show that increased soluble α2-macroglobulin protein is also present in the aqueous humor in a rat glaucoma model, as well as in the aqueous humor of human glaucoma patients but not in cataract patients. One mechanism by which α2-macroglobulin is neurotoxic is by inhibiting the neuroprotective activity of nerve growth factor via TrkA receptors.
Conclusions  This work further documents a potential novel mechanism of RGC death, and a potential biomarker or therapeutic target for glaucoma.