The complement system in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

Complement System and Potential Therapeutics in Age-Related Macular Degeneration

“…Additionally, various complement factors and MAC are localized in drusen and in compromised RPE cells of AMD eyes [46,47]. The association of genetic risk was also found in other complement genes; as such, the complement system and its components were studied as therapeutic targets [48][49][50].…”

Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option

“…Notably, regardless of the initiating pathway, AP accounts for about 80-90% of the activation of the terminal pathway [19]. Thus, overactivation of the complement system in the AP pathway is one of the major drivers of many systemic and organ specific diseases [20,21].…”

“…It is now well established that oxidized low-density lipoprotein (LDL) results in the upregulation of C-C motif chemokine receptor 2, interleukin 8, tumor necrosis factor, and VEGF and that binding of FH to these oxidized LDLs attenuates inflammation [95][96][97]. However, it remains unknown whether the presence of FH in HDL particles has a protective effect [21].…”

Role of Choline in Ocular Diseases

“…The retina is composed of multiple layers of cells that receive light and convert them to signals that are transferred to the brain [61]. There are five types of cells in the retina: photoreceptors, bipolar cells, ganglion cells, horizontal cells, and amacrine cells [62].…”