The role of receptor for advanced glycation end products (RAGE) : amyloid beta axis in retinal ganglion cell death in glaucoma

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Glaucoma encompasses a heterogeneous group of neurodegenerative processes associated with progressive damage to the resident neurons within the retina known as retinal ganglion cells (RGCs). The early stages of glaucoma are not associated with any symptoms, pain or change in sight. As a result, up to 40% of RGC loss occurs before a clinical diagnosis is made. Current treatments are effective at reducing intraocular pressure (IOP), the major risk factor for the disease, but a significant proportion of patients still experience vision loss despite treatment. Identifying new treatments that prevent RGC death caused by glaucomatous pathology is a major unmet need. The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of many chronic diseases, particularly neurodegenerative diseases such as Alzheimer’s disease (AD) in which RAGE and its ligand, amyloid beta (Aβ), have been shown to mediate neuronal loss. Interestingly, higher RAGE expression and A deposits have also been identified in the RGC layer in glaucoma. Given the current evidence for the involvement of similar underlying pathophysiological mechanisms in AD and glaucoma and that both RAGE and Aβ are linked to cell death pathways, I hypothesised that RAGE–Aβ signalling underlies RGC loss in glaucoma. To address this hypothesis, RAGE knockout (RAGE–/–) mice and wild-type (WT) control mice were exposed to acute IOP elevation. Further, the time-dependent effects of intravitreal injection of Aβ on RGC loss, retinal dysfunction and structural damage in RAGE–/– and WT mice were also investigated. In this study, RAGE–/– mice were protected against RGC loss in experimental glaucoma compared with WT mice. The potent effects of Aβ on RGC loss was significantly diminished in RAGE–/– mice compared with WT mice. These findings suggest that RAGE–Aβ is involved in RGC loss in an acute model of glaucoma. Similar experiments in other animal models of glaucoma are needed to confirm whether inhibition of RAGE–Aβ binding helps to slow the development of glaucoma.
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