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Relationship: 207

Title

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 Neuroinflammation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

N/A, Neurodegeneration

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Neuroinflammation

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
Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.	adjacent	Moderate		Allie Always (send email)	Open for citation & comment	WPHA/WNT Endorsed
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	Moderate		Arthur Author (send email)	Open for citation & comment	WPHA/WNT Endorsed

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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

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

According to its definition, neurodegeneration includes the death of neurons. Therefore, the KER describing the link between cell death and neuroinflammation is also applicable to this KER. However in neurodegenerative diseases and in Alzheimer's disease in particular, neurodegneration is associated with accumulation of modified/aggregated proteins (insoluble amyloid; hyperphosphorylated tau), which are recognised as potential triggers of neuroinflammation:

Proteinopathies associated with neurodegenerative disorders like Alzheimer’s disease (AD) and Parkinson’s disease (PD) may be sensed as damage associated molecular patterns (DAMPs) and thus activate microglia within the CNS. In animal neurodegeneration models and post-mortem brain samples from patients suffering from neurodegenerative disorders often revealed the presence of activated microglia and the accumulation of inflammatory mediators at the lesion sites, which suggests a continuous crosstalk between the brain immune system and the injured neurons during neurodegeneration. Microglial are typically activated acutely in response to an initial triggering insult, but their continued presence in large numbers around the lesion areas may actually promote neuronal death despite the absence of the initial triggering insult. Inflammatory factors being released by dying neurons and/or actively secreted from the activated microglia aid in maintaining the vicious cycle between activated microglia and damaged neurons (Thundyil and Lim 2015).

The fact that neuronal death can trigger neuroinflammation and that neuroinflammation can, in turn, cause neuronal degeneration, is known as a vicious circle, which is involved in the pathogeny of neurodegenerative diseases (Griffin et al., 1998; McGeer and Mc Geer, 1998; Blasko et al., 2004; Cacquevel et al., 2004; Barbeito et al., 2010; Rubio-Perez and Morillas-Ruiz, 2012; Thundyil and Lim, 2015).

Microglial cells are involved in the clearance of amyloid plaques (Querfurth and LaFerla, 2010), but can also be responsible for amyloid plaque formation (Streit and Sparks, 1997). As aging microglia seem to lose their ability to phagocytose (Floden and Combs, 2011), impaired clearance, as well as active deposition, can both contribute to amyloid plaque accumulation.

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

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

In Alzheimer's disease, Griffin and coworkers (1997) described the presence of reactive microglial cells inside the amyloid plaques and of reactive astrocytes around the plaques. Intra-cerebroventricular injections of beta-amyloid resulted in age-related increase in cholinergic loss and microglial activation (Nell et al., 2014). Increased neuronal expression of presequence protease (PreP) decreased the accumulation of beta-amyloid in synaptic mitochondria and decreases the neuroinflammatory response (Du Fang et al., 2015), showing a link between the accumulation of insoluble proteins and neuroinflammation. In addition, presence of the apolipoprotein E4 (APOE) allele, which is the strongest genetic risk factor for the development of Alzheimer's disease, increases microglial reactivity in the amyloid plaques of a mouse model of beta-amyloid deposition, suggesting a role for APOE in modulation beta-amyloid-induced neuroinflammation in Alzheimer's disease progression (Rodriguez et al., 2014).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Include consideration of temporal concordance here

Binding of agonists to N-methyl-D-aspartate receptor (NMDAR) in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to reduction (or loss) of cognitive function

DomA (0.75 mg/kg body weight) when administered intravenously in adult rats reveals neuronal degeneration followed by glial activation (Ananth et al., 2001; 2003). More specifically, 5 days after DomA administration, Nissl staining of brain sections derived from DomA-treated animals have shown extensive neuronal damage in the pyramidal neurons of CA1, CA3 subfields and hilus of the dentate gyrus in the hippocampus. In the same brain areas, neuroinflammation has also been evident characterised by increased GFAP and OX-42 immunoreactivity at 5 days after DomA administration but not earlier (24 h) (Ananth et al., 2003). Previously, the same research team has shown increased number of stained degenerated neurons in the hippocampus by Nissl staining as early as 24 h following the administration of DomA, however, the degeneration has been found to be more severe after 5 days (Ananth et al., 2001).

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

Gap of knowledge: there are no studies showing that glufosinate-induced neurodegeneration leads to neuroinflammation.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Quantitative evaluation of these KERs, when KEup and KEdown are measured in the same experiment in a dose and time dependent manner following exposure to DomA or GLF is not available.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

References

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

Ananth C, Thameem Dheen S, Gopalakrishnakone P, Kaur C. Domoic acid-induced neuronal damage in the rat hippocampus: changes in apoptosis related genes (bcl-2, bax, caspase-3) and microglial response. J Neurosci Res., 2001. 66: 177-190.

Ananth C, Gopalakrishnakone P, Kaur C. Protective role of melatonin in domoic acid-induced neuronal damage in the hippocampus of adult rats. Hippocampus, 2003. 13:375-87.

Barbeito AG, Mesci P, Boillee S., Motor neuron-immune interactions: the vicious circle of ALS. J Neural Transm., 2010, 117(8): 981-1000.

Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. 2004. How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Aging cell 3(4): 169-176.

Cacquevel M, Lebeurrier N, Cheenne S, Vivien D. Cytokines in neuroinflammation and Alzheimer's disease. Curr Drug Targets., 2004, 5(6): 529-534.

Fang D, Wang Y, Zhang Z, Du H, Yan S, Sun Q, et al., Increased neuronal PreP activity reduces Abeta accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model. Human molecular genetics, 2015, 24(18): 5198-5210.

Griffin.W.S.T., Sheng J, Mrak R., Inflammatory Pathways. Implications in Alzheimer's disease. Humana Press Inc., 1997, 0: 169-176.

Floden AM, Combs CK. 2011. Microglia demonstrate age-dependent interaction with amyloid-beta fibrils. J Alzheimers Dis 25(2): 279-293.

Griffin, W. S., J. G. Sheng, et al., Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol., 1998, 8(1): 65-72.

Hayward JH, Lee SJ. A Decade of Research on TLR2 Discovering Its Pivotal Role in Glial Activation and Neuroinflammation in Neurodegenerative Diseases. 2014, Experimental neurobiology, 23(2): 138-147.

McGeer PL, McGeer EG., Glial cell reactions in neurodegenerative diseases: Pathophysiology and Therapeutic Interventions. Alzheimer DisAssocDisord 12 Suppl. 1998, 2: S1-S6.

Nell HJ, Whitehead SN, Cechetto DF., Age-Dependent Effect of beta-Amyloid Toxicity on Basal Forebrain Cholinergic Neurons and Inflammation in the Rat Brain. Brain Pathol., 2015, 25(5): 531-542.

Querfurth HW, LaFerla FM. 2010. Alzheimer's disease. The New England journal of medicine 362(4): 329-344.

Rodriguez GA, Tai LM, LaDu MJ, Rebeck GW., Human APOE4 increases microglia reactivity at Abeta plaques in a mouse model of Abeta deposition. J Neuroinflammation, 2014, 11: 111.

Rubio-Perez JM, Morillas-Ruiz JM.,A review: inflammatory process in Alzheimer's disease, role of cytokines. Scientific World Journal, 2012: 756357.

Streit WJ, Sparks DL. 1997. Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. JMolMed 75: 130-138.

Thundyil J, Lim KL., DAMPs and Neurodegeneration. Ageing research reviews. 2015, 24(Pt A):17-28