Evaluation of Prion Deposits and Microglial Activation in Scrapie-Infected Mice Using Molecular Imaging Probes

Song, Pu-Jiao; Barc, Céline; Arlicot, Nicolas; Guilloteau, Denis; Bernard, Serge; Sarradin, Pierre; Chalon, Sylvie; Garreau, Lucette; Kung, Hank F.; Lantier, Frédéric; Vergote, Jackie

doi:10.1007/s11307-010-0321-1

Cited by 9 publications

(14 citation statements)

References 30 publications

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“…Thus, these three aspects of prion disease pathology appeared nearly simultaneously between 20 and 40 dpi. PrPres detection at 40 dpi in this system was 20 to 30 days earlier than in several previous studies (1,2,4,12,17,30). This might be due to the rapid tempo of the disease induced by our stock of strain 22L, which is known to induce clinical disease at 135 to 140 dpi and is about 15 days faster than our stocks of other scrapie strains, such as RML, ME7, and 79A.…”

Section: Discussioncontrasting

confidence: 44%

Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35

Tribouillard-Tanvier

Race

Striebel

et al. 2012

J Virol

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Neurodegenerative diseases are typically associated with an activation of glia and an increased level of cytokines. In our previous studies of prion disease, the cytokine response in the brains of clinically sick scrapie-infected mice was restricted to a small group of cytokines, of which IL-12p40, CCL2, and CXCL10 were present at the highest levels. The goal of our current research was to determine the relationship between cytokine responses, gliosis, and neuropathology during prion disease. Here, in time course studies of C57BL/10 mice intracerebrally inoculated with 22L scrapie, abnormal protease-resistant prion protein (PrPres), astrogliosis, and microgliosis were first detected at 40 days after intracerebral scrapie inoculation. In cytokine studies, IL-12p40 was first elevated by 60 days; CCL3, IL-1␤, and CXCL1 were elevated by 80 days; and CCL2 and CCL5 were elevated by 115 days. IL12p40 showed the most extensive increase throughout disease and was 30-fold above control levels at the terminal stage. Because of the early onset and dramatic elevation of IL-12p40 during scrapie, we investigated whether IL-12p40 contributed to the development of prion disease neuropathogenesis by using three different scrapie strains (22L, RML, 79A) to infect knockout mice in which the gene encoding IL-12p40 was deleted. We also studied knockout mice lacking IL-12p35, which combines with IL-12p40 to form active IL-12 heterodimers. In all instances, knockout mice did not differ from control mice in survival time, clinical tempo, or levels of spongiosis, gliosis, or PrPres in the brain. Thus, neither IL-12p40 nor IL-12p35 molecules were required for prion disease-associated neurodegeneration or neuroinflammation. P rion diseases, also known as transmissible spongiform encephalopathy (TSE) diseases, are infectious neurodegenerative disorders that affect both humans and animals (24). Prion diseases are characterized by spongiform degeneration of gray matter, gliosis, and accumulation of a misfolded, partially protease resistant form, PrPres (also known as PrP Sc ), of the normal cellular prion protein, PrPsen (also known as PrP C ). Activation and/or proliferation of astroglia and microglia is prominent during prion disease pathogenesis. Microglial and astroglial cells produce inflammatory mediators such as cytokines and chemokines in various neurodegenerative and infectious diseases, and all may contribute to the inflammation in prion disease (5,7,9,18,25,27,35). This neuroinflammatory reaction appears to be a host response to PrPres accumulation and associated brain cell damage. However, this neuroinflammation might also act either to increase or to decrease prion disease pathogenesis, and if so, therapeutic intervention to increase or dampen this reaction might be beneficial.Our previous study focused on the cytokine response in vitro in glial cells and in vivo in the brains of sick mice after scrapie infection (35). Despite extensive gliosis during prion disease, scrapieinfected mice showed consistent significant elevation of ...

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Section: Discussioncontrasting

confidence: 44%

Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35

Tribouillard-Tanvier

Race

Striebel

et al. 2012

J Virol

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“…In addition, the distribution of activated microglial cells was consistent with the distributions of PrP Sc and dead neurons (17,18). These observations indicate that the activation of microglial cells serves an important role in the neuropathological changes of PrP-mediated scrapie infection (19). In the present study, microglial cells were activated by treatment with PrP, as demonstrated by the cell morphological changes.…”

Section: Discussionsupporting

confidence: 86%

Effect of PrP105‑132 on the secretion of interleukin‑6 and interleukin‑8 from microglial cells inï¿½vitro

Yang

Jin

2017

Exp Ther Med

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Abstract. In the present study, the effect of prion protein (PrP) on the secretion of interleukin-6 (IL-6) and IL-8 from microglial cells in vitro and its possible underlying pathway were investigating by establishing a cell model for prion disease. Rat neuroglial cells were cultured in vitro, and were treated with 80 µM PrP peptides 105-132 (PrP105-132) only, PrP+MG132 or PrP+cyclosporin A (CsA). After 48 h, the IL-6 and IL-8 levels in the supernatant fluid of the treated cells were detected using enzyme-linked immunosorbent assay. In addition, the expression levels of nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT) were evaluated using reverse transcription-polymerase chain reaction. The results indicated that the microglial cells were activated by treatment with PrP peptides. Cell bodies were augmented and appeared to have round, rod and amoeba-like shapes. In addition, the protuberances were shortened and eventually disappeared. Furthermore, the mRNA expression levels of NF-κB and NFAT in microglial cells increased, as well as the IL-6 and IL-8 levels in the supernatant fluid after treatment with PrP. However, the mRNA expression levels of NF-κB, and the IL-6 and IL-8 levels decreased after these cells were treated with MG132, a specific inhibitor of NF-κB. The mRNA expression of NFAT decreased after these cells were treated with CsA, a specific inhibitor of NFAT; however, the IL-6 level decreased, while no significant difference was observed in the IL-8 level.In conclusion, PrP-treated microglial cells secreted IL-6 and IL-8, and the secretion of IL-6 was associated with the activation of NF-κB and NFAT pathways. In addition, the secretion of IL-8 was mainly dependent on the NF-κB pathway.

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“…From these, 22 novel radiotracers bearing carbon‐11 [11C], fluorine‐18 [18F] and iodine‐123 [123I] representing the imidazopyridines , [123I]CLINDE , [11C]CLINME and [123I]CLINME ; the structurally related imidazopyridazines , 2‐phenylpyrazolo[1,5‐a]pyrimidine acetamides and [123I] N,N‐dialkyl‐2‐phenylindol‐3‐yl‐glyoxylamides ; as well as the N‐benzyl‐N‐(2‐phenoxyaryl)‐acetamide derivatives, were prepared and extensively evaluated in rodents, with many of these compounds displaying improved biological characteristics, such as a higher target to background signal, faster clearance from nonspecific tissue and improved metabolic stability relative to [11C]PK11195 in in vivo animal studies . The imidazopyridines were the most successful; five of these radiotracers ([123I]‐CLINDE, [123I]‐CLINME, [11C]‐CLINME, [18F]‐PBR111 and [18F]‐PBR102) have further been evaluated in several rodent animal models of disease confirming that these radiotracers can image and measure activated microglia/macrophage infiltration in the CNS. In addition, we have combined and compared the results of in vitro ligand binding, autoradiography, RT‐qPCR (reverse transcription quantitative real‐time polymerase chain reaction) and immunohistochemical staining with in vivo small animal SPECT and PET imaging using our novel radiotracers [123I]CLINDE and [18F]PBR111 in models of multiple sclerosis in rodents (experimental autoimmune encephalomyelitis, EAE) .…”

Section: Tspo Ligand Developmentmentioning

confidence: 99%

The 18 kDa Translocator Protein, Microglia and Neuroinflammation

et al. 2014

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The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of "neuroinflammation" indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the "translocation" function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of "neuroinflammation."

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Evaluation of Prion Deposits and Microglial Activation in Scrapie-Infected Mice Using Molecular Imaging Probes

Abstract: These findings indicate the ability of [(125)I]-IMPY and [(125)I]-CLINDE to evaluate prion deposits and microglial activation in vitro and ex vivo in scrapie-infected mice at different stages of the disease.

Cited by 9 publications

References 30 publications

Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35

Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35

Effect of PrP105‑132 on the secretion of interleukin‑6 and interleukin‑8 from microglial cells inï¿½vitro

The 18 kDa Translocator Protein, Microglia and Neuroinflammation

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