Iron accumulation in Bruch's membrane and melanosomes of donor eyes with age-related macular degeneration

Mahroo

Progress in Retinal and Eye Research

et al. 2016

179

159

Drusen are discussed frequently in the context of their association with age-related macular degeneration (AMD). Some types may, however, be regarded as a normal consequence of ageing; others may be observed in young age groups. They also occur in a number of inherited disorders and some systemic conditions. Whilst drusen are classically located external (sclerad) to the retinal pigment epithelium, accumulations of material internal (vitread to) this layer can display a drusen-like appearance, having been variously termed pseudodrusen or subretinal drusenoid deposits. This review first briefly presents an overview of drusen biogenesis and subclinical deposit. The (frequently overlapping) subtypes of clinically detectable deposit, seen usually in the context of ageing or AMD, are then described in more detail, together with appearance on imaging modalities: these include hard and soft drusen, cuticular drusen, reticular pseudodrusen and "ghost drusen". Eye disorders other than AMD which may exhibit drusen or drusen-like features are subsequently discussed: these include monogenic conditions as well as conditions with undefined inheritance, the latter including some types of early onset drusen such as large colloid drusen. A number of systemic conditions in which drusen-like deposits may be seen are also considered. Throughout this review, high resolution images are presented for most of the conditions discussed, particularly the rarer ones, providing a useful reference library for images of the range of conditions associated with drusen-like appearances. In the final section, some common themes are highlighted, as well as a brief discussion of some future avenues for research.

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

Mahroo

Progress in Retinal and Eye Research

et al. 2016

179

159

“…Melanin eliminates ROS and acts as a chelator of metals, thus protecting young RPE cells [16,17,18]. However, cytoprotective effects are gradually lost during aging, leading to decreased antioxidant capacity and also vice versa to increased oxidative stress [19,20,21,22,23]. Melanosome differentiation and cellular pigmentation are controlled by proteins whose turnover is regulated by proteasomes [50,51,52,53].…”

Section: Discussionmentioning

confidence: 99%

“…Functional autophagy can be interpreted as a beneficial effect for preventing RPE degeneration [49,58,59]. Cleansing of lipofuscin loaded melanosomes in autophagy may be anticipated to decrease oxidative stress in aged RPE cells [22,23,26]. In young RPE cells, many other cytoprotective systems, such as antioxidant production, melanogenesis, molecular chaperone response, balanced proteolysis and DNA damage response may compensate autophagy [18,25,48,60,61,62,63].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, increased melanosomal oxygen consumption and ROS production have been observed in aged RPE cells. This in turn is estimated to occur due to melanosomal lipofuscin accumulation onto the surface of melanosomes in RPE cells [22,23,24]. Previously, it was believed that lipofuscin aggregates could not be degraded by proteasomal or lysosomal enzymes, nor transported into the extracellular space via exocytosis [25].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy Regulates Proteasome Inhibitor-Induced Pigmentation in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells

Juuti‐Uusitalo

Koskela

Kivinen

et al. 2017

IJMS

The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal degradation with MG-132 or autophagy with bafilomycin A1 increased the accumulation of premelanosomes and autophagic structures in human embryonic stem cell (hESC)-derived RPE cells. Consequently, upregulation of the autophagy marker p62 (also known as sequestosome-1, SQSTM1) was confirmed in Western blot and perinuclear staining. Interestingly, cells treated with the adenosine monophosphatedependent protein kinase activator, AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), decreased the proteasome inhibitor-induced accumulation of premelanosomes, increased the amount of autophagosomes and eradicated the protein expression of p62 and LC3 (microtubule-associated protein 1A/1B-light chain 3). These results revealed that autophagic machinery is functional in hESC-RPE cells and may regulate cellular pigmentation with proteasomes.

Experimental Eye Research

“…Studies have reported increased levels of iron in post mortem maculas of patients with AMD (Hahn et al, 2003). Specifically, iron has been shown to accumulate within Bruch’s membrane and metal-binding melanosomes in the RPE (Biesemeier et al, 2015). Moreover, patients with increased retinal iron due to aceruloplasminemia tend to develop AMD-like disease at an earlier age than the general population (Cibis et al, 1959; Dunaief et al, 2005; Wolkow et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

AMD-like retinopathy associated with intravenous iron

Song

Kanu

et al. 2016

Iron accumulation in the retina is associated with the development of age-related macular degeneration (AMD). IV iron is a common method to treat iron deficiency anemia in adults, and its retinal manifestations have not hitherto been identified. To assess whether IV iron formulations can be retina-toxic, we generated a mouse model for iron-induced retinal damage. Male C57BL/6J mice were randomized into groups receiving IV iron-sucrose (+Fe) or 30% sucrose (−Fe). Iron levels in neurosensory retina (NSR), retinal pigment epithelium (RPE), and choroid were assessed using immunofluorescence, quantitative PCR, and the Perls’ iron stain. Iron levels were most increased in the RPE and choroid while levels in the NSR did not differ significantly in +Fe mice compared to controls. Eyes from +Fe mice shared histological features with AMD, including Bruch’s membrane (BrM) thickening with complement C3 deposition, as well as RPE hypertrophy and vacuolization. This focal degeneration correlated with areas with high choroidal iron levels. Ultrastructural analysis provided further detail of the RPE/photoreceptor outer segment vacuolization and Bruch’s membrane thickening. Findings were correlated with a clinical case of a 43-year-old patient who developed numerous retinal drusen, the hallmark of AMD, within 11 months of IV iron therapy. Our results suggest that IV iron therapy may have the potential to induce or exacerbate a form of retinal degeneration. This retinal degeneration shares features with AMD, indicating the need for further study of AMD risk in patients receiving IV iron treatment.