Frontiers in Cellular Neuroscience (Apr 2016)
Retinal Remodeling And Metabolic Alterations in Human AMD
Abstract
Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression.The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this paper is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina.Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease.Major findings: 1) Evidence of metabolic instability in RPE in dry-AMD.2) Photoreceptors show clear indications of stress prior to cell death.3) Cone opsin processing by the RPE in AMD retinas may be differentially compromised vs. rod opsin.4) Müller cells in AMD exhibit alterations in metabolism and morphology consistent with other retinal degenerative diseases.5) Inner retinal neurons in AMD remodel by sprouting neurites and projecting to aberrant locations.6) Retinal remodeling occurs underneath drusen.7) Retinal remodeling occurs in the presence of cone and rod photoreceptors.
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