Abstract
Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully defined. Persistent low-grade inflammation and oxidative stress eventually lead to retinal pigment epithelium dysfunction and outer blood–retinal barrier (oBRB) breakdown. The identification of AMD susceptibility genes encoding complement factors, and the presence of inflammatory mediators in drusen, the hallmark deposits of AMD, supports the notion that immune-mediated processes are major drivers of AMD pathobiology. Complement factor H (FH), the main regulator of the alternative pathway of the complement system, may have a key contribution in the pathogenesis of AMD as it is able to regulate both inflammatory and oxidative stress responses in the oBRB. Indeed, genetic variants in the CFH gene account for the strongest genetic risk factors for AMD. In this review, we focus on the roles of inflammation and oxidative stress and their connection with FH and related proteins as regulators of both phenomena in the context of AMD.
Highlights
Introduction to AgeRelated Macular Degeneration (AMD) PathophysiologyAge-related macular degeneration (AMD) is a multifactorial, chronic, and progressive degenerative disease of the central retina characterized by a decline in sharp central vision due to the atrophy of the macula [1].It constitutes the leading cause of irreversible central visual loss in people older than 60 years old in high-income regions [2,3,4]
The polymorphism lies on CCP7, the domain involved in factor H (FH) binding to Heparan sulfate (HS) in the extracellular matrix (ECM) of the Bruch’s membrane (BrM), and to C-reactive protein (CRP), MDA, oxidized LDL (oxLDL), and apoptotic cells (Figure 3) [81]
The reduced ability to control the balance between pro- and anti-inflammatory signals associated with aging might promote a switch to chronic inflammation in the macular tissue that would be accompanied by an increased oxidative stress state
Summary
Oxidative stress increases with age due to two complementary phenomena. The increase in intracellular oxidizing products that occurs with age is accompanied by a reduced anti-oxidant capacity and cellular waste removal function. This recycling process is critical in the phototransduction pathway and results in aged POS disk membranes continuously renewed (roughly, 10% of POS are removed each day [42,43]) This process results in the accumulation of metabolic debris from incomplete POS digestion that generates lipofuscin, an end-product highly relevant in the oxidative stress-mediated damage in AMD. Oxidized products of lipofuscin such as MDA, A2E and carboxyethylpyrrole protein are present in the RPE, and in soft drusen and produce ROS when exposed to light [45] These age-related fluorophores are strong immunogenic factors that trigger immune responses that provoke the release of antibodies and autoantibodies [46]. MDA can cause RPE damage and MDA-modified proteins are known to induce inflammatory responses and are recognized by innate immunity [51,52]
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