Sub-Retinal Injection of Human Lipofuscin in the Mouse - A Model of “Dry” Age-Related Macular Degeneration?

Abstract

Lipofuscin (LF) accumulates during lifetime in the retinal pigment epithelium (RPE) and is thought to play a crucial role in intermediate and late age-related macular degeneration (AMD). In an attemt to simulate aged retina and to study response of retinal microglia and RPE cells to LF, we injected a suspension of LF into the subretinal space of adult mice. LF suspension was obtained from human donor eyes. Subretinal injection of PBS or sham injection served as a control. Eyes were inspected by autofluorescence and optical coherence tomography, by electroretinography and on histological and ultrastructural levels. Levels of cytokine mRNA were determined by quantitative PCR separately in the RPE/choroid complex and in the retina. After injection of LF, microglial cells migrated quickly into the subretinal space to close proximity to RPE cells and phagocytosed LF particles. Retinal function was affected only slightly by LF within the first two weeks. After longer time, RPE cells showed clear signs of melanin loss and degradation. Levels of mRNA of inflammatory cytokines increased sharply after injection of both PBS and LF and were higher in the RPE/choroid complex than in the retina and were slightly higher after LF injection. In conclusion, subretinal injection of LF causes an activation of microglial cells and their migration into subretinal space, enhanced expression of inflammatory cytokines and a gradual degradation of RPE cells. These features are found also in an aging retina, and subretinal injection of LF could be a model for intermediate and late AMD

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration

“…Lipofuscin has been identified as Bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), an autofluorescent toxic visual cycle metabolite that has been implicated in the progression of geographic atrophy [69]. A2E cannot be enzymatically degraded, and accumulations in RPE cells and in healthy youthful eyes are cleared by microglia, but those in elderly eyes are cleared by microglia and peripheral blood-derived macrophages [70]. When lipofuscin is exposed to blue/violet light, it produces more ROS, making it yet another source of oxidative stress [71].…”

Sialic Acid Mimetic Microglial SIGLEC Agonistic Nanoparticle: Potential to Restore Retinal Homeostasis and Regain Visual Function in AMD

“…The retinal environment is unique amongst all other CNS compartments in that it undergoes constant damaging stress, and the microglia are constantly activated in a parainflammatory state. [72] To maintain this homeostatic retinal parainflammation, the regulators of microglial function have to be tightly controlled to determine the species of microglia that predominate. The different microglial states can be M0 sentinel and resting, M1 pro-inflammatory and phagocytic, M2d antiinflammatory and proangiogenic, M2a, b anti-inflammatory and profibrotic and M2c antiinflammatory, neuroprotective and healing.…”

Crosstalk Between Microglia and Müller Glia in the Age-Related Macular Degeneration: Role and Therapeutic Value of Neuroinflammation

“…In addition, the accumulation of cellular debris in extracellular plaques and deposits of neurons can also cause chronic local inflammatory responses, which further aggravate the retinal damage. A common morphological feature among various phenotypes of AMD is the migration of microglia into the lower lumen of the retina [ 10 ]. The activated microglia can release cytokines which would further induce recruitment of Müller cells.…”