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Editors Selection IGR 16-1
Animal Models: Pathophysiology of neurodegeneration
Comment by Jeffrey Goldberg on:
51849 Induction of amyloid-β(1-42) in the retina and optic nerve head of chronic ocular hypertensive monkeys, Ito Y; Shimazawa M; Tsuruma K et al., Molecular Vision, 2012; 18: 2647-2657
Links between glaucoma and many of the other neurodegenerative diseases continue to entice and elude clinicians and scientists. Primary open–angle glaucoma and Alzheimer's disease (AD), for example, share common features of age–related risk, chronic decline in function, and focal degeneration of one population of neurons – retinal ganglion cells (RGCs) in the case of glaucoma – and some evidence suggests that glaucoma prevalence is higher in patients with AD. The search for a molecular link that underlies both diseases has similarly continued, and among many possibilities – mitchondrial dysfunction, oxidative stress, synaptic degeneration – a role in glaucoma pathogenesis for AD-linked amyloid-β (Aβ) remains a leading candidate.
The Aβ hypothesis has been fraught with conflicting data for glaucoma – Aβ is increased in rodent models but decreased in human patients' vitreous; anti-Aβ antibodies attenuate glaucoma damage in rats, but there is little mechanistic evidence for direct toxicity. Ito and colleagues now demonstrate that Aβ is increased in the nerve fiber layer and to a lesser degree the ganglion cell layer and optic nerve head of monkeys, beginning 11 weeks after elevation of IOP, while the amyloid precursor protein (APP) is decreased along a similar time course. They argue for co–localization with astrocytic markers rather than axonal markers, suggesting the expression or accumulation may be more glial than neuronal. The findings of peri-axonal rather than peri–synaptic localization, and glial rather than neuronal expression, run counter to prior hypothesized mechanisms, and this contribution to directing further study is a valuable addition.
It is probably time to consider testing anti–Aβ therapies in human patients
On the other hand, one might argue that we have data enough on the potential value of targeting Aβ in glaucoma. As animal models will only predict efficacy in humans to a limited degree, it is probably time to consider testing anti–Aβ therapies in human patients. Candidate therapeutics that have a demonstrated safety record could be targeted to the retina and/or optic nerve, and likely deserve bridging from the laboratory into human trials.
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