Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Olst, Lynn van; Rodriguez-Mogeda, Carla; Picón, Carmen; Kiljan, Svenja; James, Rachel; Kamermans, Alwin; Pol, Susanne M. A. van der; Knoop, Lydian; Michailidou, Iliana; Drost, Evelien; Franssen, Marc; Schenk, Geert J.; Geurts, Jeroen J. G.; Amor, Sandra; Mazarakis, Nicholas D.; Horssen, Jack van; Vries, Helga E. de; Reynolds, Richard; Witte, Maarten E.

doi:10.1007/s00401-021-02293-4

Cited by 59 publications

(45 citation statements)

References 59 publications

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“…While P2RY12 was significantly lower in cortical IBA1-positive microglia compared to controls. Interestingly, the other homeostatic marker—TMEM119—was not differentially expressed [ 97 ].…”

Section: Mhciimentioning

confidence: 99%

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Beyond Activation: Characterizing Microglial Functional Phenotypes

Lier

Streit

Bechmann

2021

Cells

139

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Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e. dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease.

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Section: Mhciimentioning

confidence: 99%

“…However, Van Olst et al [ 97 ] demonstrated no increased expression of CD68 in multiple sclerosis, therefore emphasizing the importance of using several markers in order to describe the microglial phenotypes as thoroughly as possible.…”

Section: Cd68mentioning

confidence: 99%

Beyond Activation: Characterizing Microglial Functional Phenotypes

Lier

Streit

Bechmann

2021

Cells

139

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“…Their processes dynamically surveil the brain microenvironment in healthy conditions ( Madry et al, 2018 ). Following injury or in disease, microglia display a strong reactive response in which they retract their processes, reduce expression of resting phenotype proteins (such as P2Y12R, Cx3CR1, and TMEM119), and take on the amoeboid morphology and phagocytic characteristics of tissue macrophages ( Lee et al, 2010 ; Salter and Stevens, 2017 ; van Olst et al, 2021 ). In this activated state, microglia can also release cytokines and other signaling molecules that induce reactive astrogliosis with a range of beneficial ( Fukumoto et al, 2019 ) or detrimental ( Liddelow et al, 2017 ) outcomes.…”

Section: Neurovascular Unit: Components and Developmentmentioning

confidence: 99%

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

Stackhouse

Mishra

2021

Front. Cell Dev. Biol.

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Neurovascular coupling is a crucial mechanism that matches the high energy demand of the brain with a supply of energy substrates from the blood. Signaling within the neurovascular unit is responsible for activity-dependent changes in cerebral blood flow. The strength and reliability of neurovascular coupling form the basis of non-invasive human neuroimaging techniques, including blood oxygen level dependent (BOLD) functional magnetic resonance imaging. Interestingly, BOLD signals are negative in infants, indicating a mismatch between metabolism and blood flow upon neural activation; this response is the opposite of that observed in healthy adults where activity evokes a large oversupply of blood flow. Negative neurovascular coupling has also been observed in rodents at early postnatal stages, further implying that this is a process that matures during development. This rationale is consistent with the morphological maturation of the neurovascular unit, which occurs over a similar time frame. While neurons differentiate before birth, astrocytes differentiate postnatally in rodents and the maturation of their complex morphology during the first few weeks of life links them with synapses and the vasculature. The vascular network is also incomplete in neonates and matures in parallel with astrocytes. Here, we review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling. We also discuss similarities between immature astrocytes during development and reactive astrocytes in disease, which are relevant to neurovascular coupling. Finally, we close by pointing out current gaps in knowledge that must be addressed to fully elucidate the mechanisms underlying neurovascular coupling maturation, with the expectation that this may also clarify astrocyte-dependent mechanisms of cerebrovascular impairment in neurodegenerative conditions in which reduced or negative neurovascular coupling is noted, such as stroke and Alzheimer’s disease.

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“…MS 2 ↓ P2Y 12 R, hyper-ramified morphology [21] EAE animal model (early phase) Pro-inflammatory CD86, CD40, MHC-II [22] TNF-α, IFN-γ, IL-…”

Section: Initial and Early White Matter Active Lesionsmentioning

confidence: 99%

Towards PET imaging of the dynamic phenotypes of microglia

Beaino

Janssen

Vugts

et al. 2021

Clinical and Experimental Immunology

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There is increasing evidence showing the heterogeneity of microglia activation in neuroinflammatory and neurodegenerative diseases. It has been hypothesized that pro-inflammatory microglia are detrimental and contribute to disease progression, while anti-inflammatory microglia play a role in damage repair and remission. The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype relies heavily upon a clearer understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. To that end, molecular imaging techniques are required to assess microglia dynamics and study their role in disease progression as well as to evaluate the outcome of therapeutic interventions. Positron emission tomography (PET) is such a molecular imaging technique, and provides unique capabilities for noninvasive quantification of neuroinflammation and has the potential to discriminate between microglia phenotypes and define their role in the disease process. However, several obstacles limit the possibility for selective in vivo imaging of microglia phenotypes mainly related to the poor characterization of specific targets that distinguish the two ends of the microglia activation spectrum and lack of suitable tracers. PET tracers targeting translocator protein 18 kDa (TSPO) have been extensively explored, but despite the success in evaluating neuroinflammation they failed to discriminate

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Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Cited by 59 publications

References 59 publications

Beyond Activation: Characterizing Microglial Functional Phenotypes

Beyond Activation: Characterizing Microglial Functional Phenotypes

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

Towards PET imaging of the dynamic phenotypes of microglia

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