Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

Abstract

Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. The disease etiopathogenesis is not understood fully, although many triggers and processes that lead to dysfunction and degeneration of the retinal pigment epithelium (RPE) already have been identified. Thus, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time. The drusen then act as inflammatory centers that trigger chronic inflammation of the subretinal space in which microglia and recruited macrophages also are involved, and the complement system is a key component. Choriocapillaris degeneration and nutritional influences are also classic elements recognized in the AMD pathophysiology. The genetic component of the disease is embodied in the recognition of the described risk or protective polymorphisms of some complement (mainly complement factor H, CFH) and ECM related genes (mainly age-related maculopathy susceptibility 2/high-temperature requirement protein A1, ARMS2/HTRA1). Carriers of the risk haplotype at ARMS2/HTRA1 have a higher risk of developing late AMD at a younger age. Finally, gut microbiota and epigenetics may play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions. Because of multiple implicated processes, different complex combinations of treatments will probably be the best option to obtain the best visual results; they in turn will differ depending on the type and spectrum of disease affecting individual patients or the disease stage in each patient at a specific moment. This will undoubtedly lead to personalized medicine for control and hopefully a future cure, which necessitates the continued unraveling of all the processes involved in the pathogenesis of AMD that must be understood to devise the combinations of treatments for different concurrent or subsequent problems.

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

“…422,423 Aging-related macular degeneration (AMD) AMD is a degenerative disease of the macula that leads to severe visual loss in the elderly population. 424 Clinically, early AMD is characterized by the deposition of lipoproteinaceous drusen on the Bruch membrane accompanied by pigmentary abnormalities in the RPE and progresses into two late forms: dry (atrophic) and wet (neovascular) AMD. 425 In the retina, senescence of the RPE, neurons, microglia, and endothelial cells accelerates AMD.…”

Pro-Inflammatory diet accounts for higher prevalence of retinopathy in diabetes participants rather than normal glucose and prediabetes: Results from NHANES, 2005–2008

“…Both DR and age-related macular degeneration are chronic inflammatory diseases that involves the activation of the microglia, monocytes-macrophages, neutrophils, and lymphocytes as well as the secretion of inflammatory mediators, including IL-6, TNF-α, MCP-1, and VEGF ( 18 , 19 ). All of these cause damage to endothelium, pericytes, and ganglion cells, which promotes vascular permeability and neovascularization ( 20 , 21 ).…”

Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment

“…After the development of new blood vessels in the retina and subretinal region, dry AMD may evolve into wet AMD (nAMD). Following advancement, these arteries result in bleeding, serum leakage, fluid retention, visual distortion, and central vision loss [16]. As a result, mitochondrial dysfunction, altered proteostasis, altered lipid homeostasis, and lack of cellular control of oxidative stress combine to create an internal feedback loop that leads to the failure of the RPE and the accumulation of abnormal misfolded proteins and abnormal lipids that will eventually form drusen.…”