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Relationship: 208

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

Neuroinflammation leads to N/A, Neurodegeneration

Upstream event

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

Neuroinflammation

Downstream event

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

N/A, Neurodegeneration

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	Low		Arthur Author (send email)	Open for citation & comment	WPHA/WNT Endorsed
Binding of Sars-CoV-2 spike protein to ACE 2 receptors expressed on brain cells (neuronal and non-neuronal) leads to neuroinflammation resulting in encephalitis	adjacent	High	Not Specified	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development
Various neuronal effects induced by elavl3, sox10, and mbp	adjacent	Moderate	Moderate	Brendan Ferreri-Hanberry (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
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	High

Life Stage Applicability

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

Term	Evidence
During brain development, adulthood and aging	High

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

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).

Sars-CoV-2 specific evidence:

Studies on post-mortem cases indicate that lymphocytes and monocytes infiltrate in brain vessel walls, exacerbating the neuronal degeneration and demyelination process (Wu et al., 2020)

The aberrant immune response characterized by a surge in cytokine levels (e.g., IL-6) derived by SARS-CoV-2 accelerates the process of neurodegeneration that may contribute to the development of neurodegenerative diseases (Debnath et al. 2020).

SARS-CoV-2 can infect human brain organoids resulting in unique metabolic changes and the death of infected and neighbouring neurons. This phenotype is accompanied by impaired synaptogenesis (Song et al., 2020) (Mesci et al, 2020).

Moreover, it is hypothesized that an autoimmune reaction mediated by the cross-reaction between viral particles and myelin basic protein may provide the driving force for neural demyelination, as part of the neurodegenerative process. This hypothesis is supported by the fact that the genome of other coronaviruses like CoV-OC43 and CoV-229E, as well as their antibodies, has been isolated from the CNS of Multiple Sclerosis (MS) patients, and coronavirus-like particles have been found in perivascular cuffs of human MS brain (Montalvan et al. 2020). In fact, the virus might lie dormant in astrocytes and oligodendrocytes and trigger the autoimmunity mediated by molecular mimicry (Mohammadi et al., 2020).

Neurons are the target cells undergoing degeneration during infection, in part due to apoptosis (de Assis et al. 2020). Intracerebral inoculation with CoV-OC43 in susceptible mice led to an acute encephalitis, with neuronal cell death by necrosis and apoptosis (Jacomy H, et al. 2006).

SARS-CoV infection causes neuronal death (even in the absence of encephalitis) in mice transgenic for human ACE2. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centres in the medulla. The absence of the host cell receptor prevents severe murine brain disease (Netland J, et al. 2008).

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

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).

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

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)

Domoic acid

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

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

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.

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?

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 KE_up to KE_down quantitatively is provided below.

Endpoints relevant for KE_up

Neuroinflammation

Endpoints relevant for KE_down

Neurodegeneration

Model and treatments

Reference

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-b1 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

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

The hypotheisis of developmental origin of Pb-induced neurodegeneration was tested and observed in Zebra fish by Lee and Freeman (2014).

References

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

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.

Sars-CoV-2-related references:

Debnath M et al. Changing dynamics of psychoneuroimmunology during COVID-19 pandemic. Brain Behav Immun Health. 2020 May;5:100096.

Jacomy H, et al. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology. (2006) 349:335–46

Mesci P et al. Sofosbuvir protects human brain organoids against SARS-CoV-2. bioRxiv. 2020. Available at: doi: https://doi.org/10.1101/2020.05.30.125856

Mohammadi S. et al. Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms. Mol Neurobiol. 2020 Dec;57(12):5263-5275.

Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K (2020) Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review. Clin Neurol Neurosurg. 2020 Jul;194:105921.

Netland J, et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008;82:7264–7275.

Song et al. Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model. bioRxiv. 2020. Available at: https://www.biorxiv.org/content/10.1101/2020.06.25.169946v1

Wu Y, et al. Nervous system involvement after infection with COVID19 and other coronaviruses. Brain Behav Immun. 2020 Jul;87:18-22.

Zanin L, et al. SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir (Wien). 2020 Jul;162(7):1491-1494.