Abstract
The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and complement, microglial accumulation with age, etc. These point to an allostatic overload, possibly due to a breakdown in self vs. non-self when endogenous compounds and structures acquire the appearance of non-self over time. The result is inflammation and inflammation-mediated cell death. While it is clear that these processes ultimately result in degeneration of retinal pigment epithelium and photoreceptor, the prevalent type of cell death contributing to the various phenotypes is unknown. Both molecular studies as well as ultrastructural pathology suggest pyroptosis, and perhaps necroptosis, are the predominant mechanisms of cell death at play, with only minimal evidence for apoptosis. Herein, we attempt to reconcile those factors identified by experimental AMD models and integrate these data with pathology observed under the electron microscope—particularly observations of mitochondrial dysfunction, DNA leakage, autophagy, and cell death.
Highlights
Age-related Macular Degeneration (AMD), a degenerative disease of the outer retina, is the leading cause of central irreversible blindness in the United States [1], accounting for 54% of all blindness in Americans of European ancestry, as well as 5% of all blindness globally [2]
An important question that needs to be answered is whether inflammation is the root cause of AMD, or if the initial events are the result of metabolic abnormalities, hypoxia, and oxidative stress, with the resulting inflammation constituting only a secondary insult which is observed once the disease has progressed to intermediate AMD or late-stage phenotypes of geographic atrophy (GA) and choroidal neovascularization (CNV)
Apoptosis is the type of cell death most invoked in the AMD literature; our ultrastructural observations support the involvement of other types such as pyroptosis where the pathways involved are initiated by inflammation and require much less cellular energy to proceed than apoptosis [81]
Summary
Age-related Macular Degeneration (AMD), a degenerative disease of the outer retina, is the leading cause of central irreversible blindness in the United States [1], accounting for 54% of all blindness in Americans of European ancestry, as well as 5% of all blindness globally [2]. The eye is an immune privileged organ owing to the unique anatomic structure of the blood-retinal barrier composed of tight junctions, the lack of direct lymphatic drainage, and the interaction of. Retinal pigment epithelial (RPE) cells have been shown to secrete factors that suppress an immune response, including TGF-β, somatostatin, thrombospondin, and pigment epithelium derived factor (PEDF) [5]. We will summarize the current body of knowledge on the immunopathological contributors to AMD and discuss the evidence for each of these components in turn. We combine these advancements with our ultrastructural observations in order to present a synthesis of an AMD etiological model. Our ultimate goal is to explore these avenues in order to facilitate the development of effective treatment and prevention tools
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