Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins

Abstract

The largest risk factor for age-related macular degeneration (ARMD) is advanced age. A prominent age-related change in the human retina is the accumulation of histochemically detectable neutral lipid in normal Bruch’s membrane (BrM) throughout adulthood. This change has the potential to have a major impact on physiology of the retinal pigment epithelium (RPE). It occurs in the same compartment as drusen and basal linear deposit, the pathognomonic extracellular, lipid-containing lesions of ARMD. Here we present evidence from light microscopic histochemistry, ultrastructure, lipid profiling of tissues and isolated lipoproteins, and gene expression analysis that this deposition can be accounted for by esterified cholesterol-rich, apolipoprotein B-containing lipoprotein particles constitutively produced by the RPE. This work collectively allows ARMD lesion formation and its aftermath to be conceptualized as a response to the retention of a sub-endothelial apolipoprotein B lipoprotein, similar to a widely accepted model of atherosclerotic coronary artery disease (CAD) (Tabas et al., 2007). This approach provides a wide knowledge base and sophisticated clinical armamentarium that can be readily exploited for the development of new model systems and the future benefit of ARMD patients.

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

“…There is compelling evidence for the production and secretion of cholesterol-containing lipids and lipoprotein particles, secreted at least partly by the RPE (7,8), that are recruited and retained in the aging Bruch's membrane (9)(10)(11)(12)(13)(14). However, there is no unifying explanation of how and why proteins are recruited and retained at the RPE/choriocapillaris interface.…”

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

“…The eyes were enucleated, and the posterior segments were fixed in 2.5% glutaraldehyde and 2% paraformaldehyde in 0.1 M cacodylate buffer with 0.08 M CaCl 2 at 4 1C. The sections of posterior eyecups were postfixed for 1.5 h in 2% aqueous OsO 4 , dehydrated in ethanol and water, and embedded in EPON. Ultrathin sections were cut from blocks and stained with saturated aqueous uranyl acetate and Sato's lead stain.…”

“…2,3 Drusen contains several pro-inflammatory components such as complement proteins, lipoproteins, oxidized lipids and double-stranded RNA (dsRNA). 4,5 Moreover, identification of genetic variations in inflammation-related genes, such as complement genes, implicates inflammation as a potential factor in AMD. 6 However, the key factors that promote inflammation in AMD and the intimate relationship between retinal inflammation and cell death remain elusive.…”

CETP Deficiency and Concerns in CETP Inhibitor Development

“…On the contrary, apoE4 is a protective factor for AMD, but it is a risk factor for CAD. Although retinal drusen and arterial plaques are both contain lipoproteins, the orientation from vascular lumen was opposite; drusen progression towards the retinal pigment epithelium is away from the choriocapillary vessels, but plaque progression was towards the vascular lumen in atherosclerosis (20). We observed a female in the seventies with complete CETP deficiency and no AMD (unpublished observation).…”