Aop:12

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Status

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AOP Title

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
Short name: Binding of antagonist to NMDARs can lead to neuroinflammation and neurodegeneration

Authors

Florianne Tschudi-Monnet, Department of Physiology, University of Lausanne, Switzerland, and Swiss Center for Applied Human Toxicology (SCAHT), Florianne.Tschudi-Monnet@unil.ch, corresponding author

Rex FitzGerald, SCAHT, Universität Basel, Missionsstrasse 64, CH-4055 Basel, Rex.FitzGerald@unibas.ch

Acknowledgments: The authors greatly acknowledged the contribution of Drs Anna Price and Magda Sachana who prepared the MIE and KE1-KE4 as well as the related KERs of this AOP.

Anna Price, Joint Research Centre Institute for Health and Consumer Protection Systems Toxicology Unit Via E. Fermi 2749 - 21020 - Ispra (VA) -Italy, e-mail address: PRICE Anna <Anna.PRICE@ec.europa.eu>

Magdalini Sachana, Joint Research Centre Institute for Health and Consumer Protection Systems Toxicology Unit Via E. Fermi 2749 - 21020 - Ispra (VA) -Italy, present e-mail address: "Magdalini.SACHANA@oecd.org" <Magdalini.SACHANA@oecd.org>

Status

Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

OECD Project 1.13: Neurotoxicant-induced Neuroinflammation: a converging key event in an adverse outcome pathway.

This AOP was last modified on 12/5/2016.

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Abstract

This AOP is an extension of AOP 13 linking NMDAR chronic inhibition during brain development to impairment of learning and memory. It links chronic NMDA receptors inhibition during brain development to Adverse Outcomes, i.e. neurodegeneration in hippocampus and cortex with amyloid plaque deposition and tau hyperphosphorylation and impairment of learning and memory, which are considered as hallmark of Alzheimer's disease. It introduces another KE, Neuroinflammation, which is involved in several neurodegenerative diseases. With Neuroinflammation and Neurodegeneration, this AOP connects to AOP 48, where in adult brain, « neuroinflammation » leads to « Neurodegeneration » ; « Neurodegeneration » leads to « Decreased neuronal network function », which finally leads to « Impairement of learning and memory ». Both neurodegeneration and cognitive deficits are observed in Alzheimer’s pathology. But as neurodegenerative diseases are complex and multifactorial, the authors proposed two Adverse outcomes: one at the organism level « Impairment of learning and memory», and one at the organ level, « neurodegeneration ». Both are regulatory endpoints. This AOP integrates in the network of AOPs relative to neurotoxicity testing.

This AOP is based on the hypothesis of Landrigan and coworkers (2005) proposing an early origin of neurodegenerative diseases in later life. The chemical initiator known to block NMDARs and used in this AOP for the empirical support is lead (Pb), which is a well-known developmental neurotoxicant. In epidemiological studies of adults, cumulative lifetime lead exposure has been associated with accelerated decline in cognition (Bakulski et al., 2012), suggesting that long term exposure to lead during brain development or occupational exposure in adulthood increases the risk to develop a neurodegenerative disease of Alzheimer's type. The long latency period between exposure and late-onset of neurodegeneration and cognitive deficits gives a very broad life stage applicability, where developmental exposure has consequences in the aging brain. Such a long temporal delay between exposure and adverse outcome is a real difficulty and challenge for neurotoxicity testing. As the Key Event « Neuroinflammation » appears to play a crucial role in the neurodegenerative process, the authors proposed to include the measurement of this apical KE in the battery of regulation-required neurotoxicity testing.

The recent review by Tartaglione and coworkers (2016) is a very good summary of the challenges and experimental studies descibed in this AOP.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
NMDA receptors, Binding of antagonist Strong

Key Events

Event Support for Essentiality
NMDARs, Inhibition Strong
Calcium influx, Decreased Strong
Release of BDNF, Reduced Moderate
Cell injury/death, N/A Strong
Neuroinflammation, N/A Moderate

Adverse Outcome

Adverse Outcome
Neurodegeneration, N/A
Learning and memory, Impairment

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
NMDA receptors, Binding of antagonist Directly Leads to NMDARs, Inhibition Strong
NMDARs, Inhibition Directly Leads to Calcium influx, Decreased Strong
Calcium influx, Decreased Directly Leads to Release of BDNF, Reduced Strong
Release of BDNF, Reduced Directly Leads to Cell injury/death, N/A Strong
Cell injury/death, N/A Directly Leads to Neuroinflammation, N/A Moderate
Neuroinflammation, N/A Directly Leads to Neurodegeneration, N/A Moderate
Neurodegeneration, N/A Directly Leads to Learning and memory, Impairment Strong

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Life Stage Applicability

Life Stage Evidence Links
During brain development

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Weak NCBI
Monkey Strong
rat Rattus sp. Strong NCBI
mouse Mus sp. Moderate NCBI
zebrafish Danio rerio Moderate NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

The aim of this AOP is to capture the KEs and KERs that occur after chronic binding of antagonist to NMDA receptors in neurons of hippocampus and cortex during brain development and that lead to neurodegeneration with impairment in learning and memory in later life. Neurodegenreation with accumulation of amyloid plaques and hyperphosphorylated tau, as well as cognitive deficit are associated to neurodegeneration of of Alzheimer's type. Currently, the hypothesis of Landrigan et al., (2005) of developmental origins of neurodegenerative diseases has been demonstrated in monkeys, in rats, mice and in zebra fish following Pb treatment (Zawia and Basha, 2005; Basha and Reddy, 2010; Bihaqui et al., 2013; Bihaqui et al., 2014 ; Lee and Freeman, 2014). There is strong agreement that Alzheimer's disease is progressive and that neurodegeneration is occuring mainly in hippocampus and cortex, associated with cognitive deficits (Schoemaker et al., 2014). This AOP uses the MIE and several KEs of the AOP 13 entitled "Binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities ", with an additional KE: neuroinflammation and two AOs: an AO at the organ level: Neurodegeneration in hippocampus and cortex and an AO at the organism level: Impairment of learning and memory. Impairment of learning and memory is the same AO than in AOP 13, but the point is that this AO is detected when the brain is aging, and it is due to neurodegeneration with accumulation of amyloid peptides and tau hyperphosphorylation. Development Pb exposure has adverse effects on cognitive functioning that can persist into adulthood and may be exacerbated with aging (Schneider et al., 2013). Such delayed effects may be due to epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases observed often at the lowest level of exposure (Schneider et al., 2013). The fact that neuroinflammation trigggered during early brain development was shown to cause Alzheimer pathology when aging (Krstic et al., 2012), suggests that chronic neuroinflammation may play a causal role in cognitive decline in aging. A recent report described a mechanistic link between chronic inflammation and aging microglia; and a causal role of aging microglia in neurodegenerative cognitive deficits: A sirtuin 1 (SIRT1) deficiency was observed in aging microglia, leading to a selective activation of IL1-β transcription mediated through hypomethylation of IL-1β proximal promoter exacerbating aging or tau-associated cognitive deficits (Cho et al. 2015). Taken together, these data suggest that Pb-induced neuroinflammation during brain development may underlie the delayed effects on cognitive deficits in aging, as depicted in the proposed AOP


Weight of Evidence Summary

Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

1. Concordance of dose-response and temporal concordance between KEs and the AO

It is difficult to analyze the dose-response relationships between the different KEs, because of the long temporal delay between MIE and AO ; because no study has analyzed them simultaneously, and because of the difficulties in extrapolating in vitro to in vivo data. As the apical KEs and AO occur and can be measured years after exposure, even when Pb blood level has returned to normal, measurement of bone Pb content has been proposed as a measurement of historical Pb exposure in adults (Bakulski et al., 2012, 2014). The following table gives an overview of the doses/concentrations and exposure duration at which the different KEs were measured.


KE1

KE2

KE3

KE4

K5

AO at organ level

AO at organism level

NMDAR inhibition

Calcium influx, decreased

BDNF release, decreased

Cell injury/death

Neuroinflammation

Neurodegeneration with amyloid plaques and tau hyperphosphorylation

Impairment of learning and memory

 

Pb 2.5-5 mM acute

inhibits

NMDAR whole cell and channel current in hippocampal neurons

 

(Alkondon et al., 1990)

Pb 100 nM 1h-24h

decrease Ca2+ in embryonic rat hippocampal neurons

 

(Ferguson et al., 2000)

no direct evidence

 

Pb 2mM in drinking water 3 weeks before mating till weaning (PND 21) resulting in

at PND 21

Pb blood 108.8 mg/L

Pb hippoc. 0.253 mg/g

at PND 91

Pb blood 39.27 mg/L

Pb hippoc. 0.196 mg/g

 

about 35% decrease in synapses in hippocampus

 

about 30% decrease of hippocampal neurons

 

(Xiao et al., 2014)

 

in vivo

0.22 ppm (together with As and Cd) from gestational day 5 till day 180

 

in adulthood: IL-1b, TNF-a, IL-6 increased 2x

 

Ahsok et al., 2015

 

Rats exposed to Pb 100 ppm for 8 weeks (from PND 24 to 80) caused at the end of treatment microglial activation in hippocampus.

(Liu et al., 2012

 

 

in vitro

 

10-6-10-4 M for 10 days

in 3D cultures of fetal rat brain cells

 

microglial and astrocyte reactivities

 

(Zurich et al., 2002)

 

co-cultures of hippocampal neurons with microglial cells treated with Pb (50 micomol/L for 48h) caused microglial activation and upregulation of IL-1beta, TNF-alpha and i_NOS

(Liu et al., 2012)

Monkeys exposed to

Pb 1.5 mg/kg/day

from birth to 400 days

 

at 23 years of age

 

Tau accumulation

Overexpression of amyloid-beta protein precursor and of amyloid-beta

enhanced pathologic neurodegeneration

 

(Bihaqi et al., 2011; Bihaqi and Zawia, 2013)

 

Mice exposed to

Pb 0.2% in drinking water from PND 1-20 or from PND 1-20 + From 3-7 months

 

at 700 days of age

 

elevated protein and mRNA for tau

and

aberrant site-specific tau hyperphosphorylation

 

(Bihaqi et al., 2014)

 

Human Tg-SWDI APP transgenic mice , PB 50 mg/kg by gavage for 6 weeks exhibit increase AB in CSF, cortex and hippocampus and increased amyloid plaque load (Gu et al., 2012)

 

Rats exposed to Pb 100 ppm for 8 weeks (from PND 24 to 80) caused at the end of treatment neuronal death in hippocampus.

(Liu et al., 2012)

 

Mice exposed to

Pb 0.2% in drinking water from PND 1-20 or from PND 1-20 + From 3-7 months

 

at 700 days of age

 

Decrease in cognitive functions (Morris water maze, Y maze testing for spatial memory and memory, a hippocampal formation-dependent task)

 

(Bihaqi et al., 2014)

 

Rats exposed to Pb 100 ppm for 8 weeks (from PND 24 to 80) reduced hippocampal LTP level at the end of the treatment

(Liu et al., 2012)

 

 

Human Tg-SWDI APP transgenic mice , PB 50 mg/kg by gavage for 6 weeks showed an impaired spatial learning (Gu et al., 2012)

 



2. Strength, consistency and association of AO and MIE

The accepted molecular mechanism of action of the chemical initiator Pb is inhibition of NMDARs (Alkondon et al., 1990; Gavazzo et al., 2001, 2008; Guilarte et al., 1992; Omelchenko et al., 1997) and several experimental studies in rat, monkey and zebra fish linked chronic exposure to Pb during brain development to Alzheimer's like neurodegeneration with cognitive deficits (Zawia and Basha, 2005; Basha and Reddy, 2010; Bihaqui et al., 2013; Bihaqui et al., 2014 ; Lee and Freeman, 2014). However, although other inhibitors of NMDARs exist, none of them except Pb has been studied for long term effects and for linking the MIE to this AO. This is certainly a weakness of this AOP to have a single chemical initiator for the empirical support.



3. Biological Plausibility, and empirical support

 

Defining Question

High /Strong

Moderate

Low/weak

Support for Biological Plausibility of KERs

Is there a mechanistic (i.e. structural or functional) relationship between KEup and KEdown consistent with established biological knowledge?

Extensive understanding of the KER based on extensive previous documentation and broad acceptance

The KER is plausible based on analogy to accept biological relationship but scientific understanding is not completely established

There is empirical support for a statistical association between KEs but the structural or functional relationship between them is not understood

MIE to KE inhibition of NMDARs

 

Extensive understanding

Limited conflicting data

 

 

KE NMDAR inhibition to KE calcium influx, decreased

 

Extensive understanding

Limitied conflicting data

 

 

KE calcium influx, decreased to KE release of BDNF, decreased

 

Extensive understanding

Limited conflicting data

 

 

KE release of BDNF, decreased to KE Cell  Injury/death

 

Extensive understanding

Limited conflicting data

 

 

KE Cell injury/death to KE Neuroinflammation

 

 

The general mechanisms linking cell injury/death to neuroinflammation is well accepted. However, it is mainly descibed in adult brain. However, a neuroinflammatory response was found following Pb exposure of 3D cultures during synaptogenesis and myelination (Zurich et al., 2002). A controversy exists about apoptosis and neuroinflammation, but some empirical evidences has been provided.

 

The fact that cell injury/deat leads to neuroinflammation and that neuroinflammation leads to neurodegeneration is known as avicious circle and is involved in neurodegenerative diseases, suggesting that neuroinflammation exacerbates the neurodegenerative process (Griffin et al., 1998; 2006)

 

 

 

KE Neuroinflammation to AO Neurodegeneration in Hippocampus and cortex

 

 

In adult, the early involvement of neuroinflammation in the neurodegenerative process is widely accepted.

 

In immature brain, one study in mice link gestational induction of neuroinflammation to late neurodegeneration with accumulation of aberrant amyloid and tau (Kristic et al., 2012).

 

 

 

There are in vitro experimental evidences following Pb exposure linking neuroinflammation to extensive neuronal death in immature cells.

In vivo, There are several studies linking early Pb exposure to late neurodegeneration in several species. However, the mechanisms involved is epignenetic modifications of genes involved in the amyloid cascade. Such epigenetic modifications may be due to ROS released by the neuroinflammatory process (Bolin et al., 2006).

Therefore the link may be indirect and needs further analyses.

 

AO Neurodegeneration in hippocampus and cortex  to AO Impairment of learning and memory

 

The role of hippocampus in memory processes is well accepted. Alterations of LTP in hippocampus of rats exposed to Pb has been described (Liu et al., 2012), as well as preferential accumulation of hyperphosphorylated tau in frontal cortex of mice exposed during development to Pb. These mice exhibited cognitive deficit when aging (Bihaqi et al., 2014).

 

 

 

 

 

 

 

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above. <html>


Table: Essentiality of KEs

2 Support for Essentiality of KEs

Defining Question

Are downstream KEs and/or the AO prevented if an upstream KE is blocked ?

High (Strong)

Moderate

Low (Weak)

Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs (e.g. stop/reversibility studies, antagonism, knock out models, etc.)

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE leading to increase in KE down or AO

No or contradictory experimental evidence of the essentiality of any of the KEs

KE1

NMDARs inhibition

STRONG

Activation of NMDAR results in LTP, which is related to increase synaptic strength and memory formation in hippocampus (Johnston et al., 2009).

KE2

Calcium influx decreased

STRONG

In CNS, many intracellular responses to modified calcium level are mediated by calcium/calmoduline-regulated protein kinases (Wayman et al., 2008). Mice with a mutation of calmoduline kinase II, which is abundantly found in hippocampus, have shown spatial learning impairment (Silva et al., 1992)

KE3

Release of BDNF, reduced

STRONG

BDNF serves essential function in synaptic plasticity (Poo, 2001) and is crucial for learning and memory processes (Lu et al., 2008). Precursor form of BDNF and mature BDNF are decreased in the preclinical stages of Alzheimer's disease (Peng et al., 2005)

KE4

Cell Injury/death, increased

STRONG

Several studies dealing with postnatal administration of NMDAR antagonists such as MK 801, ketamine or ethanol have shown a devastating cell apoptotic degeneration in several brain areas of animal models resulting in learning deficits (Creeley and Olney, 2013)

KE5

Neuroinflammation

MODERATE

Rationale: Rats treated with Pb from PND 24 to 80 showed a neuroinflammatory response associated with neuronal death in hippocampus and LTP impairment. These effects were significantly reversed by administration of minocycline, an antibiotic known to block microglial reactivity (Liu et al., 2012), demonstrating the essentiality of neuroinflammation for neurodegeneration in hippocampus and impairment of memory processes. In addition, the fact that neuroinflammation triggered during brain development by a systemic immune challenge caused Alzheimer's like pathology (Krstic et al., 2012), showed the central role of neuroinflammation in this pathology. In addition, in a mouse model of Alzheimer's disease, the blockade of microglial cell proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype by inhibiting the colony-stimulating factor 1 receptor on microglial cells, prevented synaptic degeneration and improved cognitive functions (Olmos-Alonso et al., 2016). This latter experiment has not been done during brain development. But the hypothesis is that a chronic neuroinflammation during a prolonged period increased the risk to develop an Alzheimer's neurodegenerative disease in aging (Krstic and Knuesel, 2013).

However, as other mechanisms such epigenetic modifications can lead to accumulation of amyloid plaques- and tau hyperphosphorylation-related neurodegeneration, and due to some inconsistencies of anti-inflammatory treatments as protection against the neurodegenerative process, the essentiality of Neuroinflammation was considered as moderate.

AO (at organ level)

Neurodegeneration in

 hippocampus and cortex

STRONG

Several studies descibed Pb-induced accumulation of amyloid peptides and hyperphosphorylated and Pb-induced cell injury/deathin hippocampus or decrease in hippocampal volume, what are all well accepted landmarks of Alzheimer's pathology (Lloret et al., 2015). As described in AOP 48, neurodegeneration can lead to "Decreased neuronal network function" which in turn leads to "impairment of learning and memory", which is also considered as a hallmark of Alzheimer's pathology (Schoemaker et al., 2014).

However, there is some controversy about the relationship between increased accumulation of amyloid plaques and increased cognitive deficits:  Lichtenstein and coworkers (2010) described that accumulation of amyloid plaques reaches a plateau, whereas a temporal relationship is observed between increased microglial activation, widespread degeneration (decreased hippocampal volume) and increased cognitive deficits. Therefore the essentiality for accumulation of amyloid and tau to cognitive deficits should be considered as moderate. But, as cell injury/death in hippocampus and cortex or decrease in hippocampal volume due to widespread neurodegeneration is strongly associated to impairment in learning and memory, the essentiality of this KE has been rated as strong.

 AO (at organism level)

Impairment of learning and memory

STRONG

Neurodegernerative diseases are complex and multifactorial, depend on gene-environment interactions, and have a slow temporal evolution (Sherer et al., 2002; Steece-Collier et al., 2002; Tsang and Soong, 2003); Mutter et al., 2004). Although a direct association of Pb with Alzheimer's development is not supported by epidemiological studies, a cohort study reported that bone Pb levels were associated with poor cognitive performance scores in old workers, suggesting that past Pb exposure can contribute to late cognitive deterioration (Dorsey et al., 2006). But despite the few epidemiological studies, the evidence is more solid in experimental studies (for review, see Chin-Chan et al., 2015). Cumulative organo-lead-exposed workers developped persistent brain lesions and progressive decline in cognitive functions (Stewart et al., 2006); and in a subcohort of the Veterans Affairs Normative aging study, it was found that Pb was associated with an increase in plasma homocysteine, a risk factor for cardiovascular diseases and neurodegeneration (Bakulski et al., 2014). Therefore, long term exposure to environmental toxicants such as Pb during brain development or exposure later in life can be considered as a risk factor for the development of neurodegenerative diseases in aging.

 

Quantitative Considerations

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

With an Adverse Outcome occuring after such a long delay after the MIE, it is extremely difficult to make a quantitative link, since the AO can occur when serum Pb levels have returned to normal. Bakulski and coworkers (2012) therefore proposed measuring Pb bone content as an index of historical Pb exposure. Regarding the KER "cell injury/death to neuroinflammation", it is accepted that neuronal injury may be sufficient to trigger a neuroinflammatory response. But, because of the neuroprotective or neuroreparative potential of neuroinflammation, it is possible that the consequences of neuroinflammation will be in a first step positive, with microglia expressing the M2 phenotype. After an exposure arrest and a temporal delay (Sandström et al., 2014), or in presence of cell death (Nakajima and Kohsaka, 2004; Hanish and Kettenmann, 2007), microglia can acquire the M1 neurodegenerative phenotype. Therefore, it is rather the qualitative phenotype of neuroinflammation that will induce neurodegeneration. However, a possible correlation of increased microglial reactivity, measured by PET and a decrease in hippocampal volume, measured by MRI, suggests, in advanced Alzheimer's disease, a possible link between the intensity of neuroinflammation and the neurodegenerative consequences (Lichtenstein et al., 2010).

Applicability of the AOP

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.

This AOP is not sex dependent. Regarding the life stage applicability, MIE induced during brain development can have consequences when brain is aging, according to the hypothesis proposed by Landrigan and coworkers (2005). However, it is also possible that the AO does not depend exclusively on developmental exposure, since cumulative occupational exposure also decreased cognitive functions in aging (Stewart et al., 2006).

Considerations for Potential Applications of the AOP (optional)

This AOP aims at giving a conceptual framework to mechanistically understand apical hazard, which can occur long after initial exposure; an hazard, which is not tested for in the standard neurotoxicity testing.

The KE "neuroinflammation", which is shared with other AOPs, appears to play an early and central role in the neurodegenerative process (Eikelenboom et al., 2000; Whitton, 2007; Krstic et al., 2012). Neuroinflammation is observed in most neurodegenerative diseases including Alzheimer's disease (Whitton, 2007 ; Tansey and Goldberg, 2009 ; Niranjan, 2014 ; Verthratiky et al., 2014). Neuroinflammation can also be triggered by several classes of toxicants (Monnet-Tschudi et al., 2007). Any toxicant able to trigger a neuroinflammatory response expressing the neurodegenerative M1 phenotype should be considered as a risk factor for neurodegenerative diseases. Therefore, testing for toxicant-induced neuroinflammation should be used as an endpoint in regulatory toxicology. The standard neurotoxicity testing does not require to measure any marker of neuroinflammation, except for fuel additives, where testing for a potential increase in glial fibrillary acidic protein (GFAP), as marker of astrocyte reactivity, is mandatory according to US EPA (40 CFR 79 67).

The evolution of regulation towards mechanistically-driven approaches for supporting hazard identification implies also the development of in vitro testing. Three-dimensional cultures, prepared from fetal rat brain cells, exhibiting an histotypic organization comprising all types of brain cells (specifically microglial cells and astrocytes, as effector cells of neuroinflammation) and allowing long time maintenance for repeated exposure and for studying the evolution of neuroinflammatory phenotypes are already available (Alépée et al., 2014; Monnet-Tschudi et al., 2007 ; Sandström et al., 2014). Similar 3D cultures prepared from human pluripotent stem cells are in development (Schwartz et al., 2016; Stoppini et al., in press).

References


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