Glaucoma as Neurodegeneration in the Brain

Abstract

Glaucoma, a group of diseases characterized by progressive optic nerve degeneration that results in irreversible blindness, can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence from human and animal studies have shown that glaucoma shares some common neurodegenerative pathways with Alzheimer's disease (AD) and other tauopathies, such as chronic traumatic encephalopathy (CTE) and frontotemporal dementia. This hypothesis is based on the focal adhesion pathway hypothesis and the spreading hypothesis of tau. Not only has the Apolipoprotein E (APOE) gene been shown to be associated with AD, but also with primary open angle glaucoma (POAG). This review will highlight the relevant literature in the past 20 years from PubMed that show the pathogenic overlap between POAG and AD. Neurodegenerative pathways that contribute to transsynaptic neurodegeneration in AD and other tauopathies might also be similar to those in glaucomatous neurodegeneration.

Keywords: Alzheimer’s disease; amyloid precursor protein; phosphorylated tau; primary open-angle glaucoma; tauopathy.

Figure 1

The focal adhesion complex regulates the actin cytoskeleton and downstream cell signaling pathways, such as in the spread of tau pathology. Integrin, amyloid precursor protein (APP), and receptor tyrosine kinase interact at the cell surface membrane to modulate cell adhesion. The genes for integrin, kindlin2, and CD2AP proteins regulate both APP metabolism and tau metabolism, as indicated by dashed outlines; whereas the genes for Cass4 and Pyk2 proteins are involved in only tau-related pathways and the gene for APP only in APP-related pathways. The genes for proteins inside the yellow-colored shapes are considered risk factors for AD. Adapted from Dourlen P, Kilinc D, Malmanche Net al The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol 138, 221–236 (2019). Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Figure 2

Coronal section of the left lateral geniculate nucleus in a 72-year-old patient after 8 years of optic atrophy from absolute glaucoma in the left eye. The smaller cells with less staining in ipsilateral layers 2, 3, and 5 (marked with an asterisk) represent transsynaptic atrophy. Layers 1 and 2 are the magnocellular layers. Layers 3 to 6 are the parvocellular layers. (Contrast-enhanced grayscale photo of a Nissl-stained specimen at 20x magnification; unpublished observation).