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Relationship: 2967


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Apoptosis leads to N/A, Neurodegeneration

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis adjacent High Travis Karschnik (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Rattus norvegicus Rattus norvegicus High NCBI
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

In the central nervous system (CNS), neuronal apoptosis is a physiological process that is an integral part of neurogenesis, and aberrant apoptosis has been implicated in the  pathogenesis of neurodegeneration (Okouchi et al., 2007).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

This evidence was assembled from a literature search relying on standard search engines such as PubMed, Web of Science, Google Scholar, Environmental Index, Scopus, Toxline, and Toxnet and the search strategy included terms related to metal mixtures, individual metals (e.g., arsenic, lead, manganese, and cadmium), neurodevelopmental health outcomes, and associated Medical Subject Headings (MeSH) terms.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

During the development of the nervous system, an excessive number of neurons is produced. This massive overproduction of neurons is followed by a programmed demise of  roughly one half of the originally produced cells (Okouchi et al., 2007). The precisely controlled process is referred to as naturally occurring neuronal death which is a highly conserved cellular  mechanism in diverse organisms, ranging from invertebrate species such as the nematode (Okouchi et al., 2007), Caenorhabditis elegans, and insects, to nearly all of the studied vertebrate species (Mishima et al., 1999). Natural neuronal death is be lieved to mold the nervous system’s cellular structure and function (Okouchi et al., 2007).

As axons extend, they also bifurcate with each branch forming of its own growth cone, a process that is also regulated by apoptosis (Chen et al., 2020).  Under normal conditions, a low level of caspase maintains a balance between growth cone attraction and repulsion and inhibits axon extension; however, in PTSD, apoptosis is enhanced in key brain regions and caspase activation alters growth cone trajectory and dendritic pruning, leading to axon misguidance and dendrite degeneration. The combined outcome of these processes is the formation of fewer or incorrect synapses in PTSD that are defective in information transmission and cause abnormalities in memory and  behavior (Chen et al., 2020).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

While the molecular mechanisms underlying neuronal apoptosis and diabetic encephalopathy remain unresolved, it appears that diabetes-associated perturbations in the  insulin/IGF system and hyperglycemia may play prominent roles (Li and Sima 2004).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

A. Petzold, et al. In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study Brain, 134 (Pt 2) (2011), pp. 464-483

Bao J, Cao C, Zhang X, Jiang F, Nicosia SV, and Bai W. Suppression of beta-amyloid precursor protein signaling into the nucleus by estrogens mediated through complex  formation between the estrogen receptor and Fe65. Mol Cell Biol 27: 1321–1333, 2007.

Chen, Xinzhao, et al. "Synapse impairment associated with enhanced apoptosis in post‐traumatic stress disorder." Synapse 74.2 (2020): e22134.

Chiueh C, Lee S, Andoh T, and Murphy D. Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. Endocrine 21: 27–31,  2003.

Chiueh CC, Andoh T, Lai AR, Lai E, and Krishna G. Neuroprotective strategies in Parkinson’s disease: protection against progressive nigral damage induced by free radicals.  Neurotox Res 2: 293–310, 2000.

Deigner HP, Haberkorn U, and Kinscherf R. Apoptosis modulators in the therapy of neurodegenerative diseases. Expert Opin Investig Drugs 9: 747–764, 2000.

Gandy S. Estrogen and neurodegeneration. Neurochem Res 28: 1003–1008, 2003.

Kiechle T, Dedeoglu A, Kubilus J, Kowall NW, Beal MF, Friedlander RM, Hersch SM, and Ferrante RJ. Cytochrome C and caspase-9 expression in Huntington’s disease.  Neuromolec Med 1: 183–195, 2002.

Koh PO, Won CK, and Cho JH. Estradiol prevents the injury-induced decrease of Akt/glycogen synthase kinase 3beta phosphorylation. Neurosci Lett 404: 303–308, 2006.

L. Pan, et al. Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis Development, 132 (4) (2005), pp. 703-712

Li ZG and Sima AA. C-peptide and central nervous system complications in diabetes. Exp Diabesity Res 5: 79–90, 2004.

Li ZG, Zhang W, and Sima AA. The role of impaired insulin/IGF action in primary diabetic encephalopathy. Brain Res 1037: 12–24, 2005.

Li ZG, Zhang W, Grunberger G, and Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 946: 221–231, 2002.

Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz–Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke–Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, and Neria E. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85: 1101–1108, 2003.

Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, and Okawa M. Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biol Psychiatry 45: 417–421, 1999

Okouchi, Masahiro, et al. "Neuronal apoptosis in neurodegeneration." Antioxidants & redox signaling 9.8 (2007): 1059-1096.

P.B. Pun, et al. Low level primary blast injury in rodent brain Front. Neurol., 2 (2011), p. 19

Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, and Ghiso J. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273:  7185–7188, 1998

Pappolla MA, Simovich MJ, Bryant–Thomas T, Chyan YJ, Poeggeler B, Dubocovich M, Bick R, Perry G, Cruz–Sanchez F, and Smith MA. The neuroprotective activities of  melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors. J Pineal Res 32: 135–142, 2002.

Rai, Nagendra Kumar, et al. "Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina." Toxicology and applied pharmacology 273.2 (2013): 242-258.

Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, and Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 11: 341–354, 2002

Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, and Yuan J. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22: 623–633, 1999.

Sima AA and Li ZG. The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats. Diabetes 54: 1497–1505, 2005.

Teng X, Sakai T, Liu L, Sakai R, Kaji R, and Fukui K. Attenuation of MPTP-induced neurotoxicity and locomotor dysfunction in Nucling-deficient mice via suppression of the  apoptosome pathway. J Neurochem 97: 1126–1135, 2006.

Yao M, Nguyen TV, and Pike CJ. Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide induced neuronal death. J Neurosci  27:1422–1433, 2007.

Zhang Y, McLaughlin R, Goodyer C, and LeBlanc A. Selective cytotoxicity of intracellular amyloid peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol 156: 519–529, 2002.