Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

In this report, we evaluated the role of iron in sodium iodate (NaIO₃)-induced model of age-related macular degeneration (AMD) in ARPE-19 cells in-vitro, and mouse models in-vivo. ARPE-19 cells, a human retinal pigmented epithelial cell line, were exposed to 10 mM of NaIO₃ for 24 h, and the expression and localization of major iron modulating proteins was evaluated by Western blotting (WB) and immunostaining. Synthesis and maturation of cathepsin-D (cat-D), a lysosomal enzyme, was evaluated by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) and WB respectively. For in-vivo studies, C57BL/6 mice were injected with 40 mg/kg mouse body weight of NaIO₃ intraperitoneally, and their retina was evaluated after 3 weeks as above. We observed that NaIO₃ induced a 10-fold increase in ferritin in ARPE-19 cells, which co-localized with LC3II, an autophagosomal marker, and LAMP-1, a lysosomal marker. A similar increase in ferritin was noted in retinal lysates and retinal sections of NaIO₃-injected mice by WB and immunostaining. Impaired synthesis and maturation of cat-D was also noted. Accumulated ferritin was loaded with iron, and released from retinal pigmented epithelial (RPE) cells in Perls’ and LAMP-1 positive vesicles. These observations suggest that NaIO₃ impairs lysosomal degradation of ferritin by decreasing the transcription and maturation of cat-D in RPE-19 cells. Iron-loaded ferritin accumulates in lysosomes and is released in lysosome membrane-enclosed vesicles in the extracellular milieu. Accumulation of ferritin in RPE-19 cells and fusion of ferritin-containing vesicles with adjacent photoreceptor cells is likely to create iron overload, compromising their viability. Moreover, reduced activity of cat-D is likely to promote the accumulation of other cellular debris in lysosomal vesicles, contributing to AMD-like pathology.