Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||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.||adjacent||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||adjacent||Low|
Life Stage Applicability
Key Event Relationship Description
It is well accepted that chronic neuroinflammation is involved in the pathogenesis of neurodegenerative diseases (McNaull et al., 2010; Tansey and Goldberg, 2009; Thundyil and Lim, 2015 ). Chronic neuroinflammation can cause secondary damage (Kraft and Harry, 2011). The mechanisms by which neuroinflammation (i.e. activated microglia and astrocytes) can kill neurons and induce/exacerbate the neurodegenerative process has been suggested to include the release of nitric oxide that causes inhibition of neuronal respiration, ROS and RNS production, and rapid glutamate release resulting in excitotoxic death of neurons (Brown & Bal-Price, 2003; Kraft & Harry, 2011; Taetzsch & Block, 2013). Glial reactivity is also associated with excessive production and release of pro-inflammatory cytokines that not only affect neurons, but also have detrimental feedback effects on microglia (Heneka et al., 2014). For example, sustained exposure to bacterial lipopolysaccharide (LPS) or to other pro-inflammatory mediators was shown to restrict microglial phagocytosis of misfiled and aggregated proteins (Sheng et al., 2003). Systemic immune challenge during pregnancy leading to microglial activation caused increased deposition of amyloid plaques and tau hyperphosphorylation in aged mice (Krstic et al., 2012, 2013), suggesting that neuroinflammation is involved in the amyloid plaques and neurofibrillary tangles formation. There is further evidence that the formation of neurofibrillary tangles is caused by microglial cell-driven neuroinflammation, since LPS-induced systemic inflammation increased tau pathology (Kitazawa et al., 2005).
Evidence Supporting this KER
Neuroinflammation is a component of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (Neumann, 2001) which may play a secondary or an active primary role in the disease process (Hirsch and Hunot, 2009). McNaull and coworkers (McNaull et al., 2010) suggested that early developmental onset of brain inflammation could be linked with late onset of Alzheimer’s disease. A recent paper by Krstic and coworkers (2012) showed that a systemic immune challenge during late gestation predispose mice to develop Alzheimer’s like pathology when aging, suggesting a causal link between systemic inflammation, neuroinflammation, and the onset of Alzheimer’s disease. Regarding toxicant-induced neuroinflammation, microglial/astrocyte activation and chronic neuron damage may continue for years after initial exposure (Taetsch and Block, 2013), suggesting that chronical neuroinflammation and neurodegeneration have a slow long-term temporal evolution. Ongoing neuroinflammation can be visualized in patients using the positron emission tomography (PET) ligand [11C] (R)-PK11195 (Cagnin et al., 2001). Recent genome-wide association study (GWAS) analyses of sporadic Alzheimer's disease revealed a set of genes that point to a pathogenic role of neuroinflammation in Alzheimer's disease (for review, see Heneka et al., 2014). High levels of pro-inflammatory cytokines produced by activated microglia and astrocytes are detected in the brain of Alzheimer's subjects and animal models (McGeer and McGeer, 1998; Janelsins et al., 2005).
Include consideration of temporal concordance here
Rats treated from gestation day 5 till postnatal day 180 with a mixture of Pb/Cd/As showed in early adulthood increased levels of IL-1b, IL-6 and TNF-a in hippocampus and frontal cortex associated with increased Ab levels, where Pb applied alone triggered maximal Ab induction (Ashok et al., 2015). Similarly, monkeys exposed during infancy to Pb (from birth to 400 days to 1 mg Pb /kg/day) showed in aging (23 y old) an overexpression of APP and Abeta (Bihaqi et al., 2011), and of Tau mRNA and protein (Bihaqi and Zawa, 2013). Similar observations were made in old rats (18-20 months) when exposed to Pb (0.2% in drinking water) from postnatal day 1 to 20 (Basha et al., 2005; Zawia and Basha, 2005; Bihaqi et al., 2014). This was associated with cognitive impairment, observed only if animals were exposed when young (Bihaqi et al., 2014). Perinatal exposure to Pb leading to a blood concentration of 10 mg/dl (a concentration considered as safe for human) promotes Tau phosphorylation in forebrain, cerebellum and hippocampus (Gassowska et al., 2016).
However, adult exposure may also increase the risk of neurodegeneration, as suggested by the two following studies:
- human Tg-SwD1 APP transgenic mice treated with Pb (27 mg/kg/day by gavage) for 6 weeks beginning at 8 weeks of age showed increased accumulation of Abeta and amyloid plaques (Gu et al., 2012).
- former organolead workers had increased tibia Pb level associated with peristent brain damage measured by MRI (Stewart et al., 2006).
Some in vitro and in vivo experiments show also that neuroinflammation can lead to degeneration:
- the conditioned medium of Pb-treated microglial cells (10 microM for 12h) caused the death of neuroblastoma cells (Kumawak et al., 2014).
- immature 3D cultures treated with Pb for 10 days exhibited neuroinflammation and neuronal death was exacerbated 10 days after the end of treatment, supporting the fact that neuroinflammation leads to neurodegeneration (Zurich et al., 2002).
- In vivo and in vitro experiments showed that Pb cause microglial activation, which upregulate the levels of pro-inflammatory cytokines (IL-1b, TNF-a) and of iNOS and cause neuronal injury and neuronal death in hippocampus. These effects are significantly reversed by minocycline, an antibiotic blocking microglial reactivity, showing the essential role of neuroinflammation in hippocampal neurodegeneration (Liu et al., 2012)
- gestational exposure of mouse to Pb (0.1 mM in drinking water) led at PND 21 to increased brain mRNA expression of IL-6 and glial finbrillary acidic protein (GFAP) as marker of astrogliosis, as well as of caspase 1 and NOS 2, suggesting a link between Pb-induced neuroinflammation and deletrious effects on neurons (Kasten-Jolly et al., 2011, 2012)
DomA promotes the expression of inflammatory genes in the brain, such as cyclooxygenase 2 (COX2) and the development of neurodegeneration (Ryan et al., 2005). By using COX2 inhibitors that causes decrease the appearance of DomA-induced neurodegeneration, they have concluded that neuroinflammation contributes towards the development of neurodegeneration (Ryan et al., 2011).
Uncertainties and Inconsistencies
Long-term treatments with NSAIDs (non-steroidal anti-inflammatory drugs) have a preventive effect on Alzheimer's disease development (Piertrzick and Behl, 2005; Wang et al., 2015), but such treatment has no effect or is even detrimental if administered once the disease is at an advanced stage (Lichtenstein et al., 2010), This may be due to the dual protective/destructive effects of neuroinflammation and to its complexity.
Serum Pb level negatively correlates with verbal memory score, but not with abnormal cognition in Alzheimer's disease (Park et al., 2014). Epidemiologic studies are not well-suited to accomodate the long latency period between exposures during early life and late onset of Alzheimer's disease, even if bone Pb content is an accurate measurement of historical Pb exposure in adult (Bakulski et al., 2012).
Besides neuroinflammation or effects associated with neuroinflammation, other mechanisms may be involved in neurodegeneration with Abeta and tau accumulation: Pb-induced epigenetic modifications of genes involved in the amyloid cascade or tau expression may contribute to the accumulation of Abeta and tau accumulation following developmental exposure to Pb (Zawia and Basha, 2005; Basha and Reddy, 2010). Also oxidative damage to DNA was shown to be involved in delayed effects observed in old rats (PD 600), if exposed early postanatally (PD 1 to 20) (Bolin et al., 2006)
Gap of knowledge: there are no studies showing that glufosinate-induced neuroinflammation leads to neurodegeneration.
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?
There are few studies where markers of neuroinflammation are measured simultaneously with markers of cell death and neurodegeneration. In addition, neuroinflammation is a complex KE, since the neurodegenerative consequences depend on the microglial phenotype, which has been measured only in very recent studies. An attempt to link KEup to KEdown quantitatively is provided below.
Endpoints relevant for KEup
Endpoints relevant for KEdown
Model and treatments
IL-6, IL-1b, TNF-a increased about 2x
in hippocampus and frontal cortex
Abeta 1-42 and Abeta 1-40
increased of 50%
in frontal cortex and hippocampus
Among individual metals, Pb triggered the maxiumum induction
Exposure to a mixture of arsenic (0.38 ppm), cadmium (0.098 ppm) and Pb (0.22 ppm)
or Pb alone (2.2 ppm)
Rat: from gestational day 05 to postnatal day 180.
Observation in early adulthood
Ashok et al., 2015
Modulation of IL-6, TGF-b1 and IL-1beta
Upregulation of GFAP (astrocyte reactivity)
Caspase 1 and NOS2 gene expression increased
Mouse treated with Pb (0.1mM) in drinking water from gestation-day 8 to PND21
Kasten-Jolly et al., 2011, 2012
Microglial reactivity about 3x, about 4X increase of IL-1 beta, TNF-alpha, iNOS
Blockade by minocycline (in vivo and in vitro)
About 5x increase of neuronal death in hippocampus
back to control levels in vivo and in vitro
Rat exposed to Pb (100ppm) from 24 to 80 days of age
hippocampal neurons+ microglia co-cultures (50 mmol /L Pb for 48 h)
Liu et al., 2012
Microglial and astrocyte reactivities observed at the end of the 10-day treatment
Decrease in markers of cholinergic and GABAergic neurons that was exacerbated (30-60% increased) if harvest was performed not immediately after the 10-day treatment but after another 10-day period devoid of treatment
Immature 3D cultures of fetal rat brain cells
Pb (10-6 -10-4 M) applied for 10 days followed by another period of 10 days without treatment
Zurich et al., 2002
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The hypotheisis of developmental origin of Pb-induced neurodegeneration was tested and observed in Zebra fish by Lee and Freeman (2014).
Ashok A, Rai NK, Tripathi S, Bandyopadhyay S., Exposure to As-, Cd-, and Pb-mixture induces Abeta, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats. Toxicol Sci., 2015, 143(1): 64-80.
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.
Basha MR, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA, et al. 2005. Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation. FASEB J 19(14): 2083-2084.
Basha R, Reddy GR. 2010. Developmental exposure to lead and late life abnormalities of nervous system. Indian journal of experimental biology 48(7): 636-641.
Bihaqi SW, Huang H, Wu J, Zawia NH. 2011. Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer's disease. J Alzheimers Dis 27(4): 819-833.
Bihaqi SW, Zawia NH. 2013. Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb). Neurotoxicology 39: 95-101.
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.
Bolin CM, Basha R, Cox D, Zawia NH, Maloney B, Lahiri DK, et al. 2006. Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. Faseb J 20(6): 788-790.
Brown GC, Bal-Price A., Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol., 2003, 27(3): 325-355.
Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al., In-vivo measurement of activated microglia in dementia. Lancet, 2001, 358(9280): 461-467.
Gassowska M, Baranowska-Bosiacka I, Moczydlowska J, Tarnowski M, Pilutin A, Gutowska I, et al. 2016. Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3beta and CDK5 dependent manner: Relevance to neurological disorders. Toxicology 347-349: 17-28.
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.
Heneka MT, Kummer MP, Latz E., Innate immune activation in neurodegenerative disease. Nat Rev Immunol., 2014, 14(7): 463-477.
Hirsch EC, Hunot S., Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol., 2009, 8: 382-397
Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ., Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation, 2005, 2: 23.
Kasten-Jolly J, Heo Y, Lawrence DA. 2011. Central nervous system cytokine gene expression: modulation by lead. J Biochem Mol Toxicol 25(1): 41-54.
Kasten-Jolly J, Pabello N, Bolivar VJ, Lawrence DA. 2012. Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice. Neurotoxicology 33(5): 1005-1020.
Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM., Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci., 2005, 25(39): 8843-8853.
Kraft AD, Harry GJ., Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. International Journal of Environmental research and Public Health., 2011, 8(7): 2980-3018.
Krstic, D., A. Madhusudan, et al., 2012. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation, 2012, 9: 151.
Krstic D, Knuesel I. 2013. Deciphering the mechanism underlying late-onset Alzheimer disease. Nature reviews Neurology 9(1): 25-34.
Kumawat KL, Kaushik DK, Goswami P, Basu A. 2014. Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation. Neurotoxicology 41: 143-153.
Lee J, Freeman JL. 2014. Zebrafish as a model for investigating developmental lead (Pb) neurotoxicity as a risk factor in adult neurodegenerative disease: a mini-review. Neurotoxicology 43: 57-64.
Lichtenstein MP, Carriba P, Masgrau R, Pujol A, Galea E., Staging anti-inflammatory therapy in Alzheimer's disease. Frontiers in Aging Neuroscience, 2010, 2: 142.
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.
McGeer PL, McGeer EG., Glial cell reactions in neurodegenerative diseases: Pathophysiology and therapeutic interventions. Alzheimer DisAssocDisord, 1998, 12 Suppl. 2: S1-S6.
McNaull BB, Todd S, McGuinness B, Passmore AP., Inflammation and Anti-Inflammatory Strategies for Alzheimer's Disease - A Mini-Review. Gerontology, 2010, 56: 3-14.
Neumann H., Control of Glial Immune Function by Neurons. Glia, 2001, 36: 191-199
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.
Pietrzik, C. and C. Behl., Concepts for the treatment of Alzheimer's disease: molecular mechanisms and clinical application. Int J Exp Pathol., 2005, 86(3): 173-185.
Ryan JC, Morey JS, Ramsdell JS, Van Dolah FM. Acute phase gene expression in mice exposed to the marine neurotoxin domoic acid. Neuroscience 2005. 136: 1121-1132.
Ryan JC, Cross CA, Van Dolah FM. Effects of COX inhibitors on neurodegeneration and survival in mice exposed to the marine neurotoxin domoic acid. Neurosci Lett. 2011. 487: 83-87.
Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE., Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis., 2003, 14(1): 133-145.
Stewart WF, Schwartz BS, Davatzikos C, Shen D, Liu D, Wu X, et al. 2006. Past adult lead exposure is linked to neurodegeneration measured by brain MRI. Neurology 66(10): 1476-1484.
Taetzsch T, Block ML., Pesticides, microglial NOX2, and Parkinson's disease. J Biochem Mol Toxicol., 2013, 27(2): 137-149.
Tansey MG, Goldberg MS., Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis., 2010, 37(3):510-8.
Thundyil J, Lim KL. 2015. DAMPs and neurodegeneration. Ageing research reviews 24(Pt A): 17-28.
Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, Tang SW, Yu JT (2015) Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimers Dis 44: 385-96
Zawia NH, Basha MR. 2005. Environmental risk factors and the developmental basis for Alzheimer's disease. Rev Neurosci 16(4): 325-337.
Zurich M-G, Eskes C, Honegger P, Bérode M, Monnet-Tschudi F. 2002. Maturation-dependent neurotoxicity of lead aceate in vitro: Implication of glial reactions. J Neurosc Res 70: 108-116.