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Relationship: 907


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

Degeneration of dopaminergic neurons of the nigrostriatal pathway leads to Neuroinflammation

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
Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits adjacent Moderate Moderate Andrea Terron (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

Several chemokines and chemokines receptors (fraktalkine, CD200) control the neuron-microglia interactions and a loss of this control on the side of neurons can trigger microglial reactivity without any further positive signal required (Blank and Prinz, 2013; Chapman et al., 2000; Streit et al., 2001). Upon neuronal injury, signals termed “Damage-Associated Molecular Patterns (DAMPs)” are released by damaged neurons to promote microglial reactivity (Marin-Teva et al., 2011; Katsumoto et al., 2014). These are for instance detected by Toll-like receptors (TLRs) (for review, see Hayward and Lee, 2014). TLR-2 functions as a master sensing receptor to detect neuronal death and tissue damage in many different neurological conditions including nerve transection injury, traumatic brain injury and hippocampal excitotoxicity (Hayward and Lee, 2014). Astrocytes, the other cellular actor of neuroinflammation besides microglia (Ranshoff and Brown, 2012) are also able to sense tissue injury via e.g. TLR-3 (Farina et al., 2007; Rossi, 2015), and neuronal injury can result in astrocytic activation (Efremova, 2015).

The SNpc can be particularly vulnarable to the inflammatory process; its contains more microglia than astrocytes when compared with other areas of the brain and this can promote stronger neuroinfammation (Mena et al. 2008, Kim et al. 2000).

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

Kreutzberg and coworkers (1995, 1996) showed that neuronal injury generally leads to activation of microglia and astrocytes. This is a general phenomenon: for instance it is always observed in ischemic damage (stroke; often in the form of glial activation following neuronal injury (Villa 2007)) as well as in stab or freeze injuries (Allahyari and Garcia, 2015). It is also observed regularly when neurons are killed by highly specific neurotoxicants that do not affect glia directly, such as injection of quinolinic acid or of 6-hydroxydopamine into the striatum (Hernandez-Baltazar et al., 2013; Arlicot et al., 2014). The vicious circle of neuronal injury triggering glial activation and glial activation triggering/enhancing neurodegeneration is often assumed to be a key element in the pathogenesis of neurodegenerative diseases, not just PD, but also Alzheimer's disease, prion disease and many others(Hirsch and Hunot, 2009; Tansey and Goldberg, 2009; Griffin et al., 1998; McGeer and Mc Geer, 1998; Blasko et al., 2004; Cacquevel et al., 2004; Rubio-Perez and Morillas-Ruiz, 2012; Thundyil and Lim, 2014; Barbeito et al., 2010).

Innate immune system, mainly microglia and astrocytes is primary involved in Parkinson's disease the(Lucin et al. 2009, Glass et al. 20101, Rocha et al. 2012), and neurons are knowns to actively regulate the microglia response to stress (Mott et al. 2004, Cardona et al. 2006). Presence of reactive microglia has been observed in post-mortem brain tissue from PD patients or in people following intoxication with MPTP as well as in animal models of PD (McGeer et al. 1988, Langston et al. 1999, McGeer et al. 2003, Czlonkowska et al. 1996, Walsh et al. 2011). In co-cultures of neurons and microglia neuronal damage/cell death triggers microglia activation that potentiates MPTP-induced neuronal injury (Gao et al. 2003).

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

• Triggering of glia by injured neurons may not necessarily be due to the damage of neurons, but it may also be due to released synuclein (Sanchez-Guajardo, 2010)

• In a AAV alpha-synucleinoptahy model, it was shown that cytoskeletal perturbation and accumulation of alpha-synuclein were sufficient to induce microglial reactivity, suggesting that neuroinflammation appears early in the disease process and is not a result triggered by cell death (Chung et al., 2009)

• Direct effects of toxicants on glia cannot be completely excluded. They have been reported for most toxicants in one or the other publication (rotenone, paraquat, MPP+) (Zhang et al., 2014; Rappold et al., 2011; Brooks et al., 1989). The overwhelming evidence speaks against such effects for rotenone and MPP+ (Klintworth et al., 2009), but for paraquat there is evidence of direct interaction with microglial membrane NADPH oxidase (Rappold et al., 2011).

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

Beside the rodent models, the concept of vicious circle with neuronal injury leading to neuroinflammation and neuroinflammation triggering or enhancing neurodegeneration is described in several neurodegenerative diseases in human, without any sex restriction (Hirsch and Hunot, 2009; Tansey and Goldberg, 2009; Griffin et al., 1998; McGeer and Mc Geer, 1998; Blasko et al., 2004; Cacquevel et al., 2004; Rubio-Perez and Morillas-Ruiz, 2012; Thundyil and Lim, 2014; Barbeito et al., 2010). Aging is an aggravating factor and increases the risk for developing a neurodegenerative disease (Kawas et al., 2000; Blasko et al., 2004).


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

Abdelsalam RM, Safar MM. 2015. Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFkappaB and Nrf2-antioxidant signaling pathways. J Neurochem 133(5): 700-707.

Allahyari RV, Garcia AD. 2015. Triggering Reactive Gliosis In Vivo by a Forebrain Stab Injury. Journal of visualized experiments : JoVE(100): e52825.

Annese V, Herrero MT, Di Pentima M, Gomez A, Lombardi L, Ros CM, et al. 2015. Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Brain structure & function 220(2): 703-727.

Arlicot N, Tronel C, Bodard S, Garreau L, de la Crompe B, Vandevelde I, et al. 2014. Translocator protein (18 kDa) mapping with [125I]-CLINDE in the quinolinic acid rat model of excitotoxicity: a longitudinal comparison with microglial activation, astrogliosis, and neuronal death. Molecular imaging 13: 4-11.

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

Biber K, Neumann H, Inoue K, Boddeke HW. 2007. Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci 30(11): 596-602.

Blank T, Prinz M. 2013. Microglia as modulators of cognition and neuropsychiatric disorders. Glia 61(1): 62-70.

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.

Brooks WJ, Jarvis MF, Wagner GC. 1989. Astrocytes as a primary locus for the conversion MPTP into MPP+. J Neural Transm 76(1): 1-12.

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

Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924.

Chung CY, Koprich JB, Siddiqi H, Isacson O. 2009. Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J Neurosci 29(11): 3365-3373.

Cicchetti F, Lapointe N, Roberge-Tremblay A, Saint-Pierre M, Jimenez L, Ficke BW, et al. 2005. Systemic exposure to paraquat and maneb models early Parkinson's disease in young adult rats. Neurobiol Dis 20(2): 360-371.

Chapman GA, Moores K, Harrison D, Campbell CA, Stewart BR, Strijbos PJLM. 2000. Fractalkine Cleavage from Neuronal Membrans Represents an Acute Event in Inflammatory Response to Excitotoxic Brain Damage. J Neurosc 20 RC87: 1-5.

Czerniczyniec A, Lanza EM, Karadayian AG, Bustamante J, Lores-Arnaiz S. 2015. Impairment of striatal mitochondrial function by acute paraquat poisoning. Journal of bioenergetics and biomembranes 47(5): 395-408.

Efremova L, Schildknecht S, Adam M, Pape R, Gutbier S, Hanf B, et al. 2015. Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism. Br J Pharmacol 172(16): 4119-4132.

Farina C, Aloisi F, Meinl E. 2007. Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3): 138-145.

Gao HM, Hong JS, Zhang W, Liu B. 2002. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22(3): 782-790.

Gao H, Liu B, Zhang W, Hong J (2003) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. FASEB J 17:1954–1956. doi:10.1096/fj.03-0109fje.

Glass CK, Saijo K, Winner B et al (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934. doi:10.1016/j.cell.2010.02.016.

Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A (1996) Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration 5:137–143.

Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, et al. 1998. Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 8(1): 65-72.

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

Hernandez-Baltazar D, Mendoza-Garrido ME, Martinez-Fong D. 2013. Activation of GSK-3beta and caspase-3 occurs in Nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine. PLoS One 8(8): e70951.

Hirsch EC, Hunot S. 2009. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 8(4): 382-397.

Katsumoto A, Lu H, Miranda AS, Ransohoff RM. 2014. Ontogeny and functions of central nervous system macrophages. J Immunol 193(6): 2615-2621.

Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A. 2000. Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 54(11): 2072-2077.

Kim WG, Mohney RP, Wilson B et al (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci: Off J Soc Neurosci 20:6309–6316.

Klintworth H, Garden G, Xia Z. 2009. Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release. Neurosci Lett 462(1): 1-5.

Kreutzberg GW. 1995. Microglia, the first line of defence in brain pathologies. Arzneimttelforsch 45: 357-360.

Kreutzberg GW. 1996. Microglia : a sensor for pathological events in the CNS. Trends Neurosci 19: 312-318.

Langston JW, Forno LS, Tetrud J et al (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605.

Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110–122

Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J. 2011. Microglia and neuronal cell death. Neuron glia biology 7(1): 25-40.

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

McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer's disease brains. Neurology 38:1285–1285.

McGeer PL, Schwab C, Parent A, Doudet D (2003) Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol 54:599–604. doi:10.1002/ana.10728.

Mena M a, Yébenes G d J (2008) Immune activation in brain aging and neurodegeneration: too much or too little? Neuroscientist 14:544–560. doi:10.1177/1073858408322839.

Mitra S, Chakrabarti N, Bhattacharyya A. 2011. Differential regional expression patterns of alpha-synuclein, TNF-alpha, and IL-1beta; and variable status of dopaminergic neurotoxicity in mouse brain after Paraquat treatment. J Neuroinflammation 8: 163.

Mott RT, Ait-Ghezala G, Town T et al (2004) Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia 46:369–379.

Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA. 2007. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis 25(2): 392-400.

Ransohoff RM, Brown MA. 2012. Innate immunity in the central nervous system. J Clin Invest 122(4): 1164-1171.

Rappold PM, Cui M, Chesser AS, Tibbett J, Grima JC, Duan L, et al. 2011. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci U S A 108(51): 20766-20771.

Rocha SM, Cristovão AC, Campos FL et al (2012) Astrocyte-derived GDNF is a potent inhibitor of microglial activation. Neurobiol Dis 47:407–415. doi:10.1016/j.nbd.2012.04.014

Rossi D. 2015. Astrocyte physiopathology: At the crossroads of intercellular networking, inflammation and cell death. Prog Neurobiol 130: 86-120.

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

Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson's disease. PLoS One. 2010 Jan 20;5(1):e8784.

Sandstrom von Tobel J, Zoia D, Althaus J, Antinori P, Mermoud J, Pak HS, et al. 2014. Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures. Toxicol Lett. 10.1016/j.toxlet.2014.02.001

Shan S, Hong-Min T, Yi F, Jun-Peng G, Yue F, Yan-Hong T, et al. 2011. New evidences for fractalkine/CX3CL1 involved in substantia nigral microglial activation and behavioral changes in a rat model of Parkinson's disease. Neurobiol Aging 32(3): 443-458.

Streit WJ, Conde J, Harrison JK. 2001. Chemokines and Alzheimer's disease. Neurobiol Aging 22: 909-913.

Sung YH, Kim SC, Hong HP, Park CY, Shin MS, Kim CJ, et al. 2012. Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson's disease mice. Life sciences 91(25-26): 1309-1316.

Tansey MG, Goldberg MS. 2009. Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis.

Teismann P, Sathe K, Bierhaus A, Leng L, Martin HL, Bucala R, et al. 2012. Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity. Neurobiol Aging 33(10): 2478-2490.

Thundyil J, Lim KL. 2014. DAMPs and Neurodegeneration. Ageing research reviews.

Villa P, van Beek J, Larsen AK, Gerwien J, Christensen S, Cerami A, Brines M, Leist M, Ghezzi P, Torup L. Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab. 2007 Mar;27(3):552-63

Walsh S, Finn DP, Dowd E (2011) Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson’s disease in the rat. Neuroscience 175:251–261.

Wang XJ, Zhang S, Yan ZQ, Zhao YX, Zhou HY, Wang Y, et al. 2011. Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK. Free Radic Biol Med 50(9): 1094-1106.

Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ, Zhang YJ, et al. 2011. CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease. J Neuroinflammation 8: 154.

Zhang XY, Chen L, Yang Y, Xu DM, Zhang SR, Li CT, et al. 2014. Regulation of rotenone-induced microglial activation by 5-lipoxygenase and cysteinyl leukotriene receptor 1. Brain Res 1572: 59-71.