Upstream eventN/A, Neurodegeneration
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||directly leads to||Moderate|
|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||directly leads to||Moderate|
Life Stage Applicability
How Does This Key Event Relationship Work
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 recognized 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.
Weight of Evidence
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 Support for Linkage
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).
Gap of knowledge: there are no studies showing that GLF-induced neurodegeneration leads to neuroinflammation.
Uncertainties or Inconsistencies
Quantitative Understanding of the Linkage
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.
Evidence Supporting Taxonomic Applicability
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