Cellular sources of TSPO expression in healthy and diseased brain

Nutma, Erik; Ceyzériat, Kelly; Amor, Sandra; Tsartsalis, Stergios; Millet, Philippe; Owen, David R.; Papadopoulos, Vassilios; Tournier, Benjamin B.

doi:10.1007/s00259-020-05166-2

Cited by 103 publications

(133 citation statements)

References 185 publications

(257 reference statements)

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“…However, recent clinical study with [ 11 C]ER176 ( 105 ) and [ 11 C]GE-180 ( 88 ) demonstrated a significant decrease in ligand retention in low-affinity binders, suggesting the necessity of further in vivo examination. Second, the heterogenous cellular sources of TSPO PET tracers have been demonstrated in astrocytes, endothelial cells, and vascular smooth muscle cells, in addition to microglia in both patients with AD and animal models ( 61 , 85 , 86 , 193 , 226 – 229 ) ( Figures 1A, B ) . Although conventional opinions consider microglia as major cellular source of TSPO in the central nervous system, latest study finds vascular TSPO provides major binding sites for TSPO ligands including most widely used [ 11 C]PK11195 and [ 11 C]PBR28 in normal mouse brains ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

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Section: Discussionmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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“…First, knowledge on levels and cellular localization of TSPO expression in healthy and diseased human brain largely stems from post-mortem studies using TSPO radioligands, but results are highly inconsistent [59,60]. Cellular sources of TSPO expression in healthy and diseased brain have recently been reviewed by Nutma et al [61]. In short, immunohistochemical studies for TSPO in healthy human brain revealed that TSPO is expressed in glial cells (microglia and astrocytes), oligodendrocytes and vascular endothelial cells [62,63].…”

Section: Translocator Protein 18 Kda (Tspo) -Gold Standard For Pet Imaging Of Activated Microgliamentioning

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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“…to nutritional change TSPO expression in the brain changes drastically in response to disease [30], potentially through a CpG methylation-mediated epigenetic mechanism [138]. It is therefore not surprising that TSPO expression is also sensitive to alterations in diet.…”

Section: Brain Tspo Neuroplasticity In Responsementioning

confidence: 99%

TSPO: an emerging role in appetite for a therapeutically promising biomarker

Wang

Beecher

2021

Open Biol.

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There is accumulating evidence that an obesogenic Western diet causes neuroinflammatory damage to the brain, which then promotes further appetitive behaviour. Neuroinflammation has been extensively studied by analysing the translocator protein of 18 kDa (TSPO), a protein that is upregulated in the inflamed brain following a damaging stimulus. As a result, there is a rich supply of TSPO-specific agonists, antagonists and positron emission tomography ligands. One TSPO ligand, etifoxine, is also currently used clinically for the treatment of anxiety with a minimal side-effect profile. Despite the neuroinflammatory pathogenesis of diet-induced obesity, and the translational potential of targeting TSPO, there is sparse literature characterizing the effect of TSPO on appetite. Therefore, in this review, the influence of TSPO on appetite is discussed. Three putative mechanisms for TSPO's appetite-modulatory effect are then characterized: the TSPO–allopregnanolone–GABA A R signalling axis, glucosensing in tanycytes and association with the synaptic protein RIM-BP1. We highlight that, in addition to its plethora of functions, TSPO is a regulator of appetite. This review ultimately suggests that the appetite-modulating function of TSPO should be further explored due to its potential therapeutic promise.

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Cellular sources of TSPO expression in healthy and diseased brain

Cited by 103 publications

References 185 publications

PET Imaging of Neuroinflammation in Alzheimer’s Disease

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Towards PET imaging of the dynamic phenotypes of microglia

TSPO: an emerging role in appetite for a therapeutically promising biomarker

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