The Cell and Molecular Biology of Glaucoma: Axonopathy and the Brain

Abstract

Many ophthalmologists and members of the lay public alike view glaucoma in its historical context—that is, as exclusively a disease of the eye. This view has been (and remains) overwhelmingly pervasive because the etiology of the disease involves so many factors associated with the eye: intraocular pressure (IOP), corneal thickness, optic disc morphology, and so on. Glaucoma is associated with sensitivity to IOP, and lowering IOP through either topical application of hypotensive drugs or surgery is the only form of treatment. Studies of animal models of glaucoma generally incorporate elevations in IOP as a way of mimicking the sort of injury that seems relevant to the human disease. However, although managing IOP can slow disease progression, it is not a cure, and vision loss in glaucoma often continues despite hypotensive regimens. 1 What is most damaging about glaucoma occurs outside of the eye, with degeneration of the optic nerve and its connections to the brain. This process involves the progressive loss of retinal ganglion cell (RGC) axons, some 1.5 million of which comprise the optic nerve in humans. Smaller eyes in experimental models have correspondingly fewer axons. Axon loss is followed eventually by apoptotic elimination of the RGC soma population in the retina. The rate at which degeneration progresses depends on many factors, including treatment efficacy. In the worst case, the loss of RGC neurons and their connections in the optic projection represents a substantial injury to the brain. Some 50% to 60% of the cerebral cortex spread over 40 to 45 distinct visual areas processes information from the retina via the optic nerve. In this sense, glaucoma is the premier age-related optic neuropathy and is becoming more prevalent as the population ages. Since the retina and optic nerve are part of the central nervous system, they lack the limited but intrinsic capacity of peripheral nervous system neurons for self-repair. Thus, identifying new neurocentric therapies for glaucoma is important, not only for preserving vision as the population ages, but also for translation to new treatments for other age-related brain diseases such as Alzheimer’s and Parkinson’s disease. Much of what we learn in glaucoma research from a neurobiological standpoint is now informing research for these other devastating conditions. 2