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.

The prion protein (PrP^C), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic β-cell line 1.1B4. We report expression of PrP^C on mouse pancreatic β-cells, where it promoted uptake of iron through divalent-metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP^−/−) were significantly lower than wild type (PrP^+/+) controls. Silencing of PrP^C in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin. Iron overloading, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrP^C-dependent manner. Similar observations were noted in the brain, liver, and neuroretina of iron overloaded PrP^+/+ but not PrP^−/− mice, indicating PrP^C-mediated modulation of insulin and glucose homeostasis through iron. Peripheral challenge with glucose and insulin revealed blunting of the response in iron-overloaded PrP^+/+ relative to PrP^−/− mice, suggesting that PrP^C-mediated modulation of IC iron influences both secretion and sensitivity of peripheral organs to insulin. These observations have implications for Alzheimer’s disease and diabetic retinopathy, known complications of type-2-diabetes associated with brain and ocular iron-dyshomeostasis.

Endothelial-to-mesenchyme-like transition (Endo-MT) of trabecular meshwork (TM) cells is known to be associated with primary open angle glaucoma (POAG). Here, we investigated whether the prion protein (PrP^C), a neuronal protein known to modulate epithelial-to-mesenchymal transition in a variety of cell types, is expressed in the TM, and plays a similar role at this site. Using a combination of primary human TM cells and human, bovine, and PrP-knock-out (PrP^−/−) mouse models, we demonstrate that PrP^C is expressed in the TM of all three species, including endothelial cells lining the Schlemm’s canal. Silencing of PrP^C in primary human TM cells induces aggregation of β1-integrin and upregulation of α-smooth muscle actin, fibronectin, collagen 1A, vimentin, and laminin, suggestive of transition to a mesenchyme-like phenotype. Remarkably, intraocular pressure is significantly elevated in PrP^−/− mice relative to wild-type controls, suggesting reduced pliability of the extracellular matrix and increased resistance to aqueous outflow in the absence of PrP^C. Since PrP^C is cleaved by members of the disintegrin and matrix-metalloprotease family that are increased in the aqueous humor of POAG arising from a variety of conditions, it is likely that concomitant cleavage of PrP^C exaggerates and confounds the pathology by inducing Endo-MT-like changes in the TM.

A direct correlation between brain iron and Alzheimer’s disease (AD) raises questions regarding the transport of non-transferrin-bound iron (NTBI), a toxic but less researched pool of circulating iron that is likely to increase due to pathological and/or iatrogenic systemic iron overload. Here, we compared the distribution of radiolabeled-NTBI ( ⁵⁹ Fe-NTBI) and transferrin-bound iron ( ⁵⁹ Fe-Tf) in mouse models of iron overload in the absence or presence of inflammation. Following a short pulse, most of the ⁵⁹ Fe-NTBI was taken up by the liver, followed by the kidney, pancreas, and heart. Notably, a strong signal of ⁵⁹ Fe-NTBI was detected in the brain ventricular system after 2 h, and the brain parenchyma after 24 h. ⁵⁹ Fe-Tf accumulated mainly in the femur and spleen, and was transported to the brain at a much slower rate than ⁵⁹ Fe-NTBI. In the kidney, ⁵⁹ Fe-NTBI was detected in the cortex after 2 h, and outer medulla after 24 hours. Most of the ⁵⁹ Fe-NTBI and ⁵⁹ Fe-Tf from the kidney was reabsorbed; negligible amount was excreted in the urine. Acute inflammation increased the uptake of ⁵⁹ Fe-NTBI by the kidney and brain from 2–24 hours. Chronic inflammation, on the other hand, resulted in sequestration of iron in the liver and kidney, reducing its transport to the brain. These observations provide direct evidence for the transport of NTBI to the brain, and reveal a complex interplay between inflammation and brain iron homeostasis. Further studies are necessary to determine whether transient increase in NTBI due to systemic iron overload is a risk factor for AD.

Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrP^Sc), a misfolded isoform of prion protein (PrP^C) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrP^Scand cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrP^Cis expressed on the basolateral membrane of retinal-pigment-epithelial (RPE) cells, where it mediates uptake of iron by the neuroretina. Accordingly, the neuroretina of PrP-knock-out mice is iron-deficient. In RPE19 cells, silencing of PrP^Cdecreases ferritin while over-expression upregulates ferritin and divalent-metal-transporter-1 (DMT-1), indicating PrP^C-mediated iron uptake through DMT-1. Polarization of RPE19 cells results in upregulation of ferritin by ~10-fold and β-cleavage of PrP^C, the latter likely to block further uptake of iron due to cleavage of the ferrireductase domain. A similar β-cleavage of PrP^Cis observed in mouse retinal lysates. Scrapie infection causes PrP^Scaccumulation and microglial activation, and surprisingly, upregulation of transferrin despite increased levels of ferritin. Notably, detergent-insoluble ferritin accumulates in RPE cells and correlates temporally with microglial activation, not PrP^Scaccumulation, suggesting that impaired uptake of iron by PrP^Sccombined with inflammation results in retinal iron-dyshomeostasis, a potentially toxic host response contributing to prion disease-associated pathology.