Retinal Degeneration and Alzheimer's Disease: An Evolving Link.

Ajay Ashok,Neil Rana,Aaron S Wise,Vindhya Bellamkonda,Dallas Mcdonald,Rithvik Ayyagari,Suman Chaudhary,Alexander E Kritikos,Neena Singh

doi:10.3390/ijms21197290

Ajay Ashok, Neil Rana + Show 7 more

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https://doi.org/10.3390/ijms21197290

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Abstract

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.

Highlights

Alzheimer’s disease (AD) is characterized by the gradual and progressive loss of memory and cognitive functions due to a loss of neurons in the hippocampus and, progressively, in other regions of the brain
In AD, the incomplete degradation of amyloid β (Aβ) and p-tau by microglial cells is likely to trigger the release of cytokines, which upregulate local hepcidin and iron accumulation in the brain
Inflammation initiated by Aβ and p-tau deposits due to amyloidogenic processing of amyloid precursor protein (APP) in the retina and retinal ganglion cells (RGC) is likely to increase cytokine levels, upregulating retinal hepcidin and the accumulation of iron

Summary

Introduction

Alzheimer’s disease (AD) is characterized by the gradual and progressive loss of memory and cognitive functions due to a loss of neurons in the hippocampus and, progressively, in other regions of the brain. Inflammation and oxidative stress due to brain iron dyshomeostasis are other prominent features of AD brain pathology [3,4,5] Whether these are triggered by Aβ and tau deposits or are a consequence of these changes remains unclear. Thinning of the retinal nerve fiber layer (RNFL) due to the selective death of retinal ganglion cells (RGCs) has emerged as a potential diagnostic test for AD [10,11], prompting visualization of the retina by optical coherence tomography (OCT) and functional analysis with electroretinography (ERG) Though promising, these tests lack sufficient specificity and sensitivity for broad clinical applications [12,13,14,15]

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