Soft Drusen in Age-Related Macular Degeneration: Biology and Targeting Via the Oil Spill Strategies

Abstract

AMD is a major cause of legal blindness in older adults approachable through multidisciplinary research involving human tissues and patients. AMD is a vascularmetabolic-inflammatory disease, in which two sets of extracellular deposits, soft drusen/ basal linear deposit (BLinD) and subretinal drusenoid deposit (SDD), confer risk for end-stages of atrophy and neovascularization. Understanding how deposits form can lead to insights for new preventions and therapy. The topographic correspondence of BLinD and SDD with cones and rods, respectively, suggest newly realized exchange pathways among outer retinal cells and across Bruch's membrane and the subretinal space, in service of highly evolved, eyespecific physiology. This review focuses on soft drusen/BLinD, summarizing evidence that a major ultrastructural component is large apolipoprotein B,E-containing, cholesterol-rich lipoproteins secreted by the retinal pigment epithelium (RPE) that offload unneeded lipids of dietary and outer segment origin to create an atherosclerosis-like progression in the subRPEbasal lamina space. Clinical observations and an RPE cell culture system combine to suggest that soft drusen/BLinD form when secretions of functional RPE back up in the subRPE-basal lamina space by impaired egress across aged Bruch's membrane-choriocapillary endothelium. The soft drusen lifecycle includes growth, anterior migration of RPE atop drusen, then collapse, and atrophy. Proof-of-concept studies in humans and animal models suggest that targeting the ''Oil Spill in Bruch's membrane'' offers promise of treating a process in early AMD that underlies progression to both end-stages. A companion article addresses the antecedents of soft drusen within the biology of the macula.

The Fate and Prognostic Implications of Hyperreflective Crystalline Deposits in Nonneovascular Age-Related Macular Degeneration

“…52,53 The main component of soft drusen is loosely packed UC-rich whorls with EC lakes, together considered ''membranous debris'' by Sarks et al 12,54 This material was later termed ''lipoprotein-derived debris'' 55 owing to multiple lines of evidence that it is derived from large apoB, E-lipoproteins secreted by the RPE, in a constitutive program of outer retinal lipid cycling. 55,56 In contrast, histologic studies of late AMD eyes demonstrate cholesterol crystals in avascular fibrosis, serous PED, hemorrhagic PED, and fibrovascular scar, which the current clinical imaging data support. The hypothesized unifying feature in these conditions is the replacement of lipidrich soft druse contents with either fluid or a fibrotic material that is sufficiently hydrated to allow UC supersaturation and precipitation.…”

“…It is true that soft drusen are a rich source of lipids that are modifiable to become proinflammatory and proangiogenic moieties that elicit local and systemic immune response. 56 However, RPE that is capable of maintaining a soft druse through physiologic secretions is probably also able to maintain photoreceptors. Recent cell culture experiments testing the effects of crystal exposure on nonconfluent RPEderived cell lines have as yet uncertain relevance to our overall pathophysiology model which is based on longitudinal clinical imaging and histology.…”

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

“…Cholesterol dysregulation leads to a myriad of pathological conditions 14 ; S2R was recently suggested as a novel player in cholesterol intracellular transport 3 . To the best of our knowledge, the current report is the first to reveal a BETs-governed epigenetic control of S2R expression.…”

Dyslipidemia in retinal metabolic disorders

“…Although the exact mechanism of drusen formation is unclear, Bruch's membrane, found between the choriocapillaris and RPE, thickens due to accumulation of oxidized lipids, lipid‐related molecules, and inflammatory debris preceding drusen formation. This slows down nutrient and waste transportation between RPE cells and choroidal vessels, leading to malfunction of RPE cells (Sarks et al , ; Curcio, ,b).…”