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Relationship: 1069


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

N/A, Neurodegeneration leads to Impairment, Learning and memory

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
Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging adjacent High Arthur Author (send email) Open for citation & comment WPHA/WNT Endorsed
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis adjacent High Cataia Ives (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 Do not cite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
Mus musculus Mus musculus Moderate NCBI
Rattus norvegicus Rattus norvegicus Moderate NCBI
Homo sapiens Homo sapiens 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
Old Age 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

Animal models of neurodegenerative diseases, in particular Alzheimer's disease, contributed to the elucidation of the link between amyloid protein and tau hyperphosphorylation and cognitive deficits. Bilateral injections of amyloid-b peptide in the frontal cortex of rats leads to progressive decline in memory and neurodegeneration in hippocampus (for review see Eslamizade et al., 2016). Recent findings have shown that soluble forms of Ab rather than insoluble forms (fibrils and plaques) are associated with memory impairment in early stages of Alzheimer's disease (for review see Salgado-Puga and Pena-Ortega, 2015). Several lines of evidence suggest that the small oligomeric forms of Ab and tau may act synergistically to promote synaptic dysfunction in Alzheimer's disease (for review see Guerrerro-Minoz et al., 2015). Some reports proposed the concept of imbalance between production and clearance of Ab42 and related Ab peptides, as an initiating factor inducing hyperphosphorylation of tau and leading to neuritic dystrophy and synaptic dysfunction (for review see Selkoe and Hardy, 2016). Recent trials of three different antibodies against amyloid peptides have suggested a slowing of cognitive decline in post hoc analyses of mild Alzheimer subjects (for review see Selkoe and Hardy, 2016). Therefore cognitive deficits may be related to the level and extent of classical Alzheimer pathology landmarks, but it is also influenced by neurodegeneration (for review see Braskie and Thompson, 2013). Indeed decreased hippocampal volume due to widespread neurodegeneration and visualized by neuroimaging appears to be a significant predictor of memory decline  (for review see Braskie and Thompson, 2016).

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.

In July 2023 updates were made to the then empty Taxonomic, Sex, and Life Stage Applicability fields and in the Empirical Evidence field with the addition of Wozniak et al., (2004), Allison et al., (2021), and Huang et al., (2012) studies.

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

It is well accepted that impairment of cell function or cell loss in hippocampus will interfere with memory processes, since the hippocampus plays a key role in memory (Barker and Warburton, 2011). In Alzheimer's disease, hippocampus and entorhinal cortex are affected early in the disease process and cognitive deficit is correlated with brain atrophy (for review Braskie and Thompson, 2013).

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

There are some inconsistencies regarding the time of exposure. Some papers clearly show that early Pb exposure increases amyloid and tau pathology and cognitive decline in aging. But few studies have addressed this complex question by using an ad hoc experimental design. Other studies have descibed the effects of lifetime or long-term exposure on cognitive functions but without a precise desciption of exposure onset and duration.

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

Allison, Samantha L., et al. "Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age." Neurobiology of aging 102 (2021): 151-160.

Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A, 3rd, et al. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA normative aging study. Environ Health Perspect 122(10): 1066-1074.

Barker GR, Warburton EC. 2011. When is the hippocampus involved in recognition memory? J Neurosci 31(29): 10721-10731.

Bihaqi SW, Bahmani A, Subaiea GM, Zawia NH. 2014. Infantile exposure to lead and late-age cognitive decline: relevance to AD. Alzheimer's & dementia : the journal of the Alzheimer's Association 10(2): 187-195.

Braskie MN, Thompson PM. 2013. Understanding cognitive deficits in Alzheimer's disease based on neuroimaging findings. Trends in cognitive sciences 17(10): 510-516.

Eslamizade MJ, Madjd Z, Rasoolijazi H, Saffarzadeh F, Pirhajati V, Aligholi H, et al. 2016. Impaired Memory and Evidence of Histopathology in CA1 Pyramidal Neurons through Injection of Abeta1-42 Peptides into the Frontal Cortices of Rat. Basic and clinical neuroscience 7(1): 31-41.

Gu H, Robison G, Hong L, Barrea R, Wei X, Farlow MR, et al. 2012. Increased beta-amyloid deposition in Tg-SWDI transgenic mouse brain following in vivo lead exposure. Toxicol Lett 213(2): 211-219.

Gu H, Wei X, Monnot AD, Fontanilla CV, Behl M, Farlow MR, et al. 2011. Lead exposure increases levels of beta-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice. Neurosci Lett 490(1): 16-20.

Guerrero-Munoz MJ, Gerson J, Castillo-Carranza DL. 2015. Tau Oligomers: The Toxic Player at Synapses in Alzheimer's Disease. Frontiers in cellular neuroscience 9: 464.

Huang, Lining, et al. "Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ–ERK signaling pathway in the developing brain." Brain research 1476 (2012): 164-171.

Liu MC, Liu XQ, Wang W, Shen XF, Che HL, Guo YY, et al. 2012. Involvement of microglia activation in the lead induced long-term potentiation impairment. PLoS One 7(8): e43924.

Park JH, Lee DW, Park KS, Joung H. 2014. Serum trace metal levels in Alzheimer's disease and normal control groups. American journal of Alzheimer's disease and other dementias 29(1): 76-83.

Salgado-Puga K, Pena-Ortega F. 2015. Cellular and network mechanisms underlying memory impairment induced by amyloid beta protein. Protein and peptide letters 22(4): 303-321.

Schneider JS, Anderson DW, Talsania K, Mettil W, Vadigepalli R. 2012. Effects of developmental lead exposure on the hippocampal transcriptome: influences of sex, developmental period, and lead exposure level. Toxicol Sci 129(1): 108-125.

Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine 8(6): 595-608.

Wozniak, David F., et al. "Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults." Neurobiology of disease 17.3 (2004): 403-414.