Aop:17

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://training.aopwiki.org/aops/17

AOP Title

Binding to SH/selen-proteins can trigger neuroinflammation leading to neurodegeneration
Short name: Neuroinflammation to Neurodegeneration 2

Authors

Florianne Tschudi-Monner, Department of Physiology, University of Lausanne, Switzerland, and Swiss Center for Applied Human Toxicology (SCAHT), Florianne.Tschudi-Monnet@unil.ch

Status

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Under development: Do not distribute or cite.

OECD Project 1.13: Neurotoxicant-induced Neuroinflammation: a converging key event in an adverse outcome pathway.

This AOP was last modified on 12/5/2016.

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Abstract

This AOP describes the cascade of events initiated by binding to selenoproteins causing a depletion of glutathione (GSH), one of the most important anti-oxidants in the brain. This will lead to oxidative stress which is deleterious to neurons. Neuroinflammation, characterized by microglial and astrocyte reactivity, will be triggered in response to neuronal damage. When neuroinflammation induces a 'neurodegenerative phenotype' associated with the production of pro-inflammatory cytokines and the expression of specific microglial markers, it can lead to neurodegeneration, the adverse outcome. Neurodegeneration will amplify the inflammatory response and lead to a self-sustained neuroinflammation that exacerbates the neurodegenerative process. Such a self-sustained neuroinflammation-neurodegenerative loop is involved in neurodegenerative diseases such as Alzheimer's and Parkinson’s diseases.

This AOP is relevant for neurotoxicity and developmental neurotoxicity testing following low dose and long term exposure and for delayed adverse outcome, according to the Landrigan et al (2005) hypothesis of early origins of neurodegenerative disease in later life. It is part of a broader effort initiated by JRC/Seurat to describe several AOPs relevant for neurotoxicity, that will be published in « Critical Reviews in Toxicology ». Currently, the only related endpoint for regulatory purposes is measurement of rodent brain glial fibrillary acidic protein (GFAP), whose increase is a marker of astrocyte reactivity; this is required by the US EPA for fuel additives, but is optional for other chemical hazard evaluations.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
SH-/selen-proteins, Binding Strong

Key Events

Event Support for Essentiality
Interferences with SH-/selen-proteins, N/A Strong
GSH, Depletion Strong
Oxidative stress, N/A Strong
Neuronal dysfunction, N/A Strong
Neuroinflammation, N/A Strong

Adverse Outcome

Adverse Outcome
Neurodegeneration, N/A

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
SH-/selen-proteins, Binding Directly Leads to Interferences with SH-/selen-proteins, N/A Strong
Interferences with SH-/selen-proteins, N/A Directly Leads to GSH, Depletion Moderate
GSH, Depletion Indirectly Leads to Oxidative stress, N/A Strong
Oxidative stress, N/A Directly Leads to Neuronal dysfunction, N/A Moderate Moderate
Neuronal dysfunction, N/A Directly Leads to Neuroinflammation, N/A Strong Moderate
Neuroinflammation, N/A Directly Leads to Neurodegeneration, N/A Strong Weak
Neurodegeneration, N/A Directly Leads to Neuroinflammation, N/A Strong Weak

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

Weight of Evidence Summary

Summary Table
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In the AOP "Neuroinflammation to Neurodegeneration 1" (no.976057), binding to components of the electron transport chain (ETC) in mitochondria leads to oxidative stress, which causes neuronal dysfunction. In the AOP "Neuroinflammation to Neurodegeneration 2" (no.678683), binding to selenoproteins in nervous tissue leads to a decrease of anti-oxidant protection and thus to oxidative stress, which causes neuronal dysfunction. In the AOP "Neuroinflammation to Neurodegeneration 3" (no.348359), agonist binding to NMDAR triggers oxidative stress, which causes neuronal dysfunction. In the AOP "Neuroinflammation to neurodegeneration 4" (no.515292), antagonist binding to NMDAR triggers neuronal dysfunction and microglial /astroglial activation. From these 4 pathways, it becomes clear that neuronal dysfunction is a broad category including a variety of events, appearing alone or concomitantly, such as synapse impairment/loss, cytoskeletal dysfunction (axonal retraction, cytoskeletal instabilities), apoptosis or necrosis. Each of these events is able to trigger a neuroinflammatory response, that may have different characteristics and express different phenotypes. And depending on the extent of the dysfunction/lesion and on the temporal evolution, neuroinflammation may evolve into neurodegeneration. In turn, neurodegeneration exacerbates the neuroinflammatory process in a self-sustained aggravation loop, playing a key role in the onset and progression of several neurodegenerative diseases. The separate AOP entitled "Multiples MIEs trigger neuroinflammation leading to neurodegeneration" (no.1435) includes AOPs 1 to 4 and identifies neuroinflammation as a converging key event.'


Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Quantitative Considerations

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Applicability of the AOP

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