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 article 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.
Highlights
This manuscript adds to the literature supporting alterations of the retinal pigment epithelium (RPE) including RPE cell thinning underneath drusen and alterations observed in aging/diseased human retinas and ties these changes to the presence of other subsequent retinal changes and most notably, retinal remodeling
These changes are by definition, pathology and result in a progressive, irreversible neural degeneration reflected by loss of retinal neurons and glia in age-related macular degeneration (AMD)
The pathologies begin with the earliest indications of cell stress identified early through metabolic instability in the RPE and in photoreceptors as well as Müller glia
Summary
Given that age-related macular degeneration (AMD) is effectively a deafferentation of the neural retina caused by the death of photoreceptors, our goal with this study was to explore whether or not AMD retinas exhibited the same retinal plasticity and remodeling observed in retinitis pigmentosa (RP; Li et al, 1995; de Raad et al, 1996; Fletcher and Kalloniatis, 1996; Fariss et al, 2000; Machida et al, 2000; Strettoi and Pignatelli, 2000; Strettoi et al, 2002, 2003; Jones et al, 2003, 2005, 2006, 2011, 2012; Marc and Jones, 2003; Marc et al, 2003, 2005, 2007, 2008; Cuenca et al, 2004; Jones and Marc, 2005; Pu et al, 2006; Aleman et al, 2007). In AMD, these defects arise from from identified defects in CFH (Boon et al, 2009), ARMS2 (Fritsche et al, 2008; Friedrich et al, 2011), HTRA1 (Dewan et al, 2006), oxidative stress (Kunchithapautham et al, 2014) and inflammation (Ozaki et al, 2014) that result in pathologies manifesting from the molecular levels to tissue levels In both dry and wet forms of AMD, photoreceptors die which we hypothesized initiates the same cascade of neural cell death and plasticity observed in other retinal degenerative diseases such as RP. This remodeling occurs underneath obvious regions of pathology like underneath drusen, and in regions where cone and rod photoreceptors are still present suggesting implications for altered retinal processing prior to photoreceptor cell death
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