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Journal of Glaucoma:
doi: 10.1097/IJG.0b013e3182934af6
Chapters

Alzheimer’s Disease and Glaucoma: Mechanistic Similarities and Differences

Ghiso, Jorge A. PhD*,†; Doudevski, Ivo PhD*; Ritch, Robert PhD; Rostagno, Agueda A. PhD*

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Erratum
Article Outline

Erratum

In the chapter that appeared on page S36 in the “Proceedings of the 18th Annual Optic Nerve Rescue and Restoration Think Tank” supplement, the author names Ivo Doudevski, PhD, Robert Ritch, MD, and Agueda A. Rostagno, PhD, were omitted. The author byline should have read:

Jorge A. Ghiso, PhD, Ivo Doudevski, PhD, Robert Ritch, PhD, and Agueda A. Rostagno, PhD

The authors’ affiliation details are:

Ivo Doudevski, PhD

Research Scientist

Department of Pathology

NYU Langone Medical Center

New York, NY

USA

Robert Ritch, MD

Shelley and Steven Einhorn Distinguished Chair in Ophthalmology

Chief, Glaucoma Service

Surgeon Director

The New York Eye & Ear Infirmary

New York, NY

USA

Agueda A. Rostagno, PhD

Associate Professor

NYU School of Medicine

New York, NY

USA

Additionally, the report of funding by NIH Grant: R21EY019129 was omitted.

Journal of Glaucoma. 22(7):597-598, September 2013.

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Author Information

Departments of *Pathology

Psychiatry, New York University Langone Medical Center

Department of Ophthalmology, Shelley and Steven Einhorn Clinical Research Center,The New York Eye & Ear Infirmary, New York, NY

Supported by NIH grants AG030539 and R21EY019129.

Disclosure: The author declares no conflict of interest.

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia. Intraneuronal neurofibrillary tangles, extracellular Aβ amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy, and synaptic and neuronal loss co-exist in the brain parenchyma, with the limbic areas being the most severely affected. The classic clinical findings are personality changes, progressive cognitive dysfunction, and loss of ability to perform activities of daily living. Visual impairment is common and appears related to disease severity, suggesting that visual testing may provide a method of screening and tracking AD changes. Although still not fully understood, research and clinical findings point to a possible common causal relationship between AD and glaucoma. These two chronic neurodegenerative disorders share biological and mechanistic features, among them (1) a strong age-related incidence, (2) retinal ganglion cell degeneration, and (3) extracellular fibrillar deposits in exfoliation syndrome, the most common recognizable cause of glaucoma, suggesting that both diseases may originate from similar misfolding mechanisms. A presentation of common pathogenetic pathways associated with these disorders, including cell death mechanisms, reactive oxygen species (ROS) production, mitochondrial dysfunction and vascular abnormalities, will serve as an initiation point for further exploration.

Glaucoma is an age-related, progressive, degenerative disorder of the optic nerve characterized by death of retinal ganglion cells (RGCs), leading to a characteristic pattern of visual field loss and cupping of the optic nerve head.1 Recent neuropathological evidence has also detected neurodegenerative lesions in the intracranial optic nerve, the lateral geniculate nucleus and the visual cortex,2,3 suggesting that glaucoma should be grouped under the broad umbrella of neurodegenerative disorders. This notion is supported by its shared features with these disorders in general, with Alzheimer’s disease (AD) in particular.

AD is a progressive neurodegenerative disorder characterized by neuronal and synaptic loss in the cerebral cortex leading to cognitive impairment, behavioral deficits and dementia. Late-onset sporadic AD is most prevalent, affecting as many as half of the U.S. population over 85 years, whereas early-onset familial forms of the disease account only for about 5% of the total cases. In both instances, extracellular deposits of β-amyloid (Aβ) in the form of parenchymal plaques and cerebral amyloid angiopathy co-exist with intraneuronal accumulations of hyperphosphorylated tau (neurofibrillary tangles). Cognitive areas, particularly the hippocampus, are most severely affected.4,5 Although largely overlooked, visual impairment is also a common finding in AD patients, with a number of reports suggesting that it may result from undiagnosed glaucoma.6 Whereas some studies have demonstrated that AD patients exhibit optic nerve degeneration and loss of RGCs, the pathogenetic relationship between both disorders remains obscure. Certain biological features are shared by both diseases; e.g., loss of specific neuronal populations, induction of similar mechanisms of cell injury and deposition of protein aggregates in specific anatomical areas. The association of the two clinical entities inferred from these observations is poorly supported by epidemiological reports, with conflicting results indicating either a higher prevalence of glaucoma in AD cases compared to controls or no difference between both groups.6

The loss of specific neuronal populations is perhaps the most fundamental process shared by glaucoma and AD. Visual dysfunction in glaucoma primarily results from the death of RGCs with axonal degeneration extending to the brain.7 In neurodegenerative disorders, compromise of specific neuronal subsets is also observed. While in Parkinson’s disease, the selective loss of nigrostriatal dopaminergic neurons manifests as progressive movement disorders,8 the loss of hippocampal and cortical neurons translates into memory and cognitive impairment in AD.9 Neuronal loss in glaucoma as well as in many neurodegenerative disorders has been associated with apoptosis, a form of programmed cell death. Although the key initiating mechanism(s) still remain unknown, a plethora of pathological processes leading to this type of cell injury have been linked to these disorders; e.g., mitochondrial dysfunction, oxidative stress, release of inflammatory mediators, glutamate excitotoxicity, and abnormal accumulations of misfolded proteins.10–13 Although it is unclear whether all these mechanisms act independently or synergistically, they are undoubtedly key participants in AD and Parkinson’s disease.14,15

Through the oxidative phosphorylation pathway, mitochondria play a central role in the production of adenosine triphosphate (ATP). The organelle dysfunction with electron leakage from the process of oxidative phosphorylation results in decline of ATP production and generation of reactive oxygen species (ROS) including superoxides, hydrogen peroxides and hydroxyl radicals, all highly reactive with DNA and proteins. ROS also interact with nitric oxide to form peroxynitrite, thereby mediating protein nitration with modification of tyrosine residues and generation of nitrotyrosine, a footprint of oxidative injury found in several neurodegenerative diseases, including AD.16 In addition, ROS influence mitochondrial inner membrane potential and Ca+2 homeostasis, releasing pro-apoptotic factors that trigger caspase activation, a central component of apoptosis induction. In glaucoma, generation of ROS-modified proteins can be demonstrated along the optic nerve, nitrotyrosine modified proteins are abundant in the vascular lining of retinal blood vessels, and levels of physiological antioxidants and superoxide scavengers are significantly reduced.10,12

Mitochondrial dysfunction also increases the susceptibility of neurons to excitotoxicity, a form of cell death resulting from excessive stimulation of neurons by excitatory amino acids, e.g., glutamate, the major neurotransmitter in the brain. Key events in this process involve the loss of Ca+2 homeostasis and activation of N-methyl-Aspartate (NMDA) receptor channels, allowing the influx of toxic calcium ions. Excitotoxicity seems to be an important mechanism in a number of neurodegenerative conditions, including Parkinson’s and AD.17

Intracellular and/or extracellular accumulation of misfolded proteins is a key feature of several neurodegenerative disorders. Soluble precursors of the deposited aggregates/fibrils are usually present in biological fluids, whereas intermediate conformations of these molecules have been recently implicated in the mechanisms of neurotoxicity. This process is well studied in AD, where multiple structural conformations of Aβ have been identified. As illustrated in Figure 1, Aβ is normally found in biological fluids and brain interstitial fluid as a soluble monomeric component and it is also the main fibrillar constituent of the brain deposits. Increasing data indicate that neither the soluble forms nor the deposited fibrils exert neurotoxicity, whereas intermediate conformations – typically composed of low molecular mass oligomers and short protofibrils of less than 200 μm in length – are now considered to be the likely neurotoxic species that trigger cell death through the mechanisms delineated above.18 Although this type of structure has not been described yet in glaucoma patients, the existence of misfolded protein aggregates has been documented in RGCs.10,12

FIGURE 1
FIGURE 1
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Since many reports are limited to non-biochemically characterized deposits, many of them from single case reports, or describing the association with inflammation-related components, the importance of these findings for the disease pathogenesis is difficult to assess. Nevertheless, it is important to note that with the exception of exfoliation syndrome, the most identifiable cause of open-angle glaucoma, the levels of protein aggregation observed in glaucoma cases never reached the severe magnitude associated with most neurodegenerative disorders.

Ultrastructural and proteomic analyses of exfoliation material have unveiled a complex mixture of extracellular matrix glycoproteins and proteoglycans heavily cross-linked and assembled in a supramolecular fibrillar structure,19,20 suggesting that similar misfolding mechanisms as those occurring in AD may take place in patients with exfoliative glaucoma. Notably, Aβ and exfoliation fibrils not only differ in their biochemical compositions but also in their structural dimensions. As comparatively illustrated in the atomic force microscopy analysis shown in Figure 2, Aβ fibrils are 6-8 nm wide (Panel A), as all described amyloid fibrils, whereas exfoliation fibers are 30-50 nm wide and exhibit a defined periodicity. Whether exfoliation fibrils or pre-fibril intermediates are the structures inducing cell injury mechanisms similar to those described in AD remains to be elucidated.

FIGURE 2
FIGURE 2
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Overall, there is lack of evidence that visual impairment observed in AD is related to glaucoma. Although both diseases share a number of mechanisms associated with cell death, it remains to be clarified whether they are primary or secondary elements in the disease pathogenesis.

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REFERENCES

1. Shields MB, Ritch R, Krupin T .Ritch R, Shields MB, Krupin T .Classification and mechanisms of the glaucomas.The Glaucomas. Chapter 40. 1989; .St. Louis:CV Mosby Co.

2. Yucel YH, Zhang Q, Gupta N, et al .Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma.Arch Ophthalmol. 2000; 118:378–384.

3. Yucel YH, Zhang Q, Weinreb RN, et al .Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleous and visual cortex in glaucoma.Prog Retin Eye Res. 2003; 22:465–481.

4. Rostagno A, Holton JL, Lashley T, et al .Cerebral amyloidosis: Amyloid subunits, mutants and phenotypes.Cell Mol Life Sci. 2010; 67:581–600.

5. Rostagno A, Lal R, Ghiso J .Dawbarn D, Allen S .Protein misfolding, aggregation, and fibril formation: Common features of cerebral and non-cerebral amyloid diseases.The Neurobiology of Alzheimer’s disease. 2007; .Oxford, United Kingdom:Oxford University Press; 133–160.

6. Kirby E, Bandelow S, Hogervorst E .Visual impairment in Alzheimer’s disease: A critical review.J Alzheimer’s Dis. 2010; 21:15–34.

7. Gupta N, Ang LC, Noel de Tilly L, et al .Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex.Br J Ophthalmol. 2006; 90:674–678.

8. Halliday G, Lees A, Stern M .Milestones in Parkinson’s disease--clinical and pathologic features.Mov Disord. 2011; 26:1015–1021.

9. Duyckaerts C, Delatour B, Potier MC .Classification and basic pathology of Alzheimer’s disease.Acta Neuropathol. 2009; 118:5–36.

10. Gupta N, Yucel YH .Glaucoma as a neurodegenerative disease.Curr Opinion Opththalmol. 2007; 18:110–114.

11. Quigley HA .Neuronal death in glaucoma.Prog Retin Eye Res. 1999; 18:39–57.

12. Ray K, Mookherjee S .Molecular complexity of primary open angle glaucoma: Current concepts.J Genet. 2009; 88:451–467.

13. Nakamura T, Lipton SA .Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: Potential implications for Alzheimer’s and Parkinson’s diseases.Apoptosis. 2010; 15:1354–1363.

14. Gorman AM .Neuronal cell death in neurodegenerative diseases: Recurring themes around protein handling.J Cell Mol Med. 2008; 12:2263–2280.

15. Nunomura A, Moreira PI, Lee HG, et al .Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases.CNS Neurol Disord Drug Targets. 2007; 6:411–423.

16. Sultana R, Perluigi M, Butterfield DA .Protein oxidation and lipid peroxidation in brain subjects with Alzheimer’s disease: Insights into mechanism of neurodegeneration from redox proteomics.Antioxid Redox Signal. 2006; 8:2021–2037.

17. Sonkusare SK, Kaul CL, Ramarao P .Dementia of Alzheimer’s disease and other neurodegenerative disorders - memantine, a new hope.Pharmacol Res. 2005; 51:1–17.

18. Walsh DM, Selkoe DJ .A beta oligomers - a decade of discovery.J Neurochem. 2007; 101:1172–1184.

19. Ovodenko B, Rostagno A, Neubert TA, et al .Proteomic analysis of exfoliation deposits.Invest Ophthalmol Vis Sci. 2007; 48:1447–1457.

20. Ritch R, Schlötzer-Schrehardt U .Exfoliation syndrome.Surv Ophthalmol. 2001; 45:265–315.

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