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Subtype and regional-specific neuroinflammation in sporadic creutzfeldt-jakob disease.

Llorens F, López-González I, Thüne K, Carmona M, Zafar S, Andréoletti O, Zerr I, Ferrer I - Front Aging Neurosci (2014)

Bottom Line: The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls.Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD.Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical School, Georg-August University , Göttingen , Germany ; Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat , Barcelona , Spain.

ABSTRACT
The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls. Deregulated genes include pro- and anti-inflammatory cytokines, toll-like receptors, colony stimulating factors, cathepsins, members of the complement system, and members of the integrin and CTL/CTLD family with particular regional and sCJD subtype patterns. Analysis of cytokines and mediators at protein level shows expression of selected molecules and receptors in neurons, in astrocytes, and/or in microglia, thus suggesting interactions between neurons and glial cells, mainly microglia, in the neuroinflammatory response in sCJD. Similar inflammatory responses have been shown in the tg340 sCJD MM1 mice, revealing a progressive deregulation of inflammatory mediators with disease progression. Yet, inflammatory molecules involved are subjected to species differences in humans and mice. Moreover, inflammatory-related cell signaling pathways NFκB/IKK and JAK/STAT are activated in sCJD and sCJD MM1 mice. Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD. Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD.

No MeSH data available.


Related in: MedlinePlus

Region-specific expression of glial cell markers in sCJD MM1 mouse model is shown. (A) Western blot analysis of GFAP in the cortex and cerebellum of control and sCJD MM1 mice at different dpi. A 10−1 inoculum dilution was performed in animals sacrificed at 210 dpi. qPCR analysis of (B) Gfap, (C) lif and Cntf, and (D) Iba1 in the cortex and cerebellum of control and MM1-inoculated mice at different dpi. 10−1 and 10−2 inoculum dilutions were performed in animals sacrificed at 210 and 240 dpi, respectively. Values are normalized using Xpnpep1 as internal controls. Between three and six animals were analyzed for each time-point and condition. Note increased expression of these markers with disease progression. Data are represented as the mean SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control cases (Tukey’s post hoc test).
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Figure 6: Region-specific expression of glial cell markers in sCJD MM1 mouse model is shown. (A) Western blot analysis of GFAP in the cortex and cerebellum of control and sCJD MM1 mice at different dpi. A 10−1 inoculum dilution was performed in animals sacrificed at 210 dpi. qPCR analysis of (B) Gfap, (C) lif and Cntf, and (D) Iba1 in the cortex and cerebellum of control and MM1-inoculated mice at different dpi. 10−1 and 10−2 inoculum dilutions were performed in animals sacrificed at 210 and 240 dpi, respectively. Values are normalized using Xpnpep1 as internal controls. Between three and six animals were analyzed for each time-point and condition. Note increased expression of these markers with disease progression. Data are represented as the mean SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control cases (Tukey’s post hoc test).

Mentions: In the cortex of MM1 mice, astrogliosis, as measured by Gfap mRNA and GFAP protein expression, was evidenced at symptomatic but not at pre-symptomatic stages. In the cerebellum, increased Gfap mRNA and GFAP protein expression was observed at late disease stages (180 dpi) (Figures 6A,B). Lif and Cntf mRNAs, and the activated microglial marker Iba1 mRNA, were also up-regulated in the CJD MM1 mice (Figures 6C,D). Microglial and astroglial activation is in agreement with mRNA up-regulation of several cytokines and mediators of the immune response at clinical stages measured with TaqMan PCR assays in sCJD MM1 the cortex of mouse brain when compared to controls (Table 2). Only IL1β was up-regulated and IL6 down-regulated at pre-clinical stages (Table 2). Interestingly, IL1β was not up-regulated at late stages in the CJD MM1 mice in agreement with IL1β levels in human samples. Several cytokines and mediators were up-regulated at late stages of disease, such as Tnfa, Tnfrs1a, C3ar1, C4b, and Tlr7, all of them also up-regulated in human samples. However, contrary to that seen in human samples anti-inflammatory cytokines were not up-regulated in CJD MM1 mice.


Subtype and regional-specific neuroinflammation in sporadic creutzfeldt-jakob disease.

Llorens F, López-González I, Thüne K, Carmona M, Zafar S, Andréoletti O, Zerr I, Ferrer I - Front Aging Neurosci (2014)

Region-specific expression of glial cell markers in sCJD MM1 mouse model is shown. (A) Western blot analysis of GFAP in the cortex and cerebellum of control and sCJD MM1 mice at different dpi. A 10−1 inoculum dilution was performed in animals sacrificed at 210 dpi. qPCR analysis of (B) Gfap, (C) lif and Cntf, and (D) Iba1 in the cortex and cerebellum of control and MM1-inoculated mice at different dpi. 10−1 and 10−2 inoculum dilutions were performed in animals sacrificed at 210 and 240 dpi, respectively. Values are normalized using Xpnpep1 as internal controls. Between three and six animals were analyzed for each time-point and condition. Note increased expression of these markers with disease progression. Data are represented as the mean SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control cases (Tukey’s post hoc test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120692&req=5

Figure 6: Region-specific expression of glial cell markers in sCJD MM1 mouse model is shown. (A) Western blot analysis of GFAP in the cortex and cerebellum of control and sCJD MM1 mice at different dpi. A 10−1 inoculum dilution was performed in animals sacrificed at 210 dpi. qPCR analysis of (B) Gfap, (C) lif and Cntf, and (D) Iba1 in the cortex and cerebellum of control and MM1-inoculated mice at different dpi. 10−1 and 10−2 inoculum dilutions were performed in animals sacrificed at 210 and 240 dpi, respectively. Values are normalized using Xpnpep1 as internal controls. Between three and six animals were analyzed for each time-point and condition. Note increased expression of these markers with disease progression. Data are represented as the mean SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control cases (Tukey’s post hoc test).
Mentions: In the cortex of MM1 mice, astrogliosis, as measured by Gfap mRNA and GFAP protein expression, was evidenced at symptomatic but not at pre-symptomatic stages. In the cerebellum, increased Gfap mRNA and GFAP protein expression was observed at late disease stages (180 dpi) (Figures 6A,B). Lif and Cntf mRNAs, and the activated microglial marker Iba1 mRNA, were also up-regulated in the CJD MM1 mice (Figures 6C,D). Microglial and astroglial activation is in agreement with mRNA up-regulation of several cytokines and mediators of the immune response at clinical stages measured with TaqMan PCR assays in sCJD MM1 the cortex of mouse brain when compared to controls (Table 2). Only IL1β was up-regulated and IL6 down-regulated at pre-clinical stages (Table 2). Interestingly, IL1β was not up-regulated at late stages in the CJD MM1 mice in agreement with IL1β levels in human samples. Several cytokines and mediators were up-regulated at late stages of disease, such as Tnfa, Tnfrs1a, C3ar1, C4b, and Tlr7, all of them also up-regulated in human samples. However, contrary to that seen in human samples anti-inflammatory cytokines were not up-regulated in CJD MM1 mice.

Bottom Line: The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls.Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD.Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical School, Georg-August University , Göttingen , Germany ; Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat , Barcelona , Spain.

ABSTRACT
The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls. Deregulated genes include pro- and anti-inflammatory cytokines, toll-like receptors, colony stimulating factors, cathepsins, members of the complement system, and members of the integrin and CTL/CTLD family with particular regional and sCJD subtype patterns. Analysis of cytokines and mediators at protein level shows expression of selected molecules and receptors in neurons, in astrocytes, and/or in microglia, thus suggesting interactions between neurons and glial cells, mainly microglia, in the neuroinflammatory response in sCJD. Similar inflammatory responses have been shown in the tg340 sCJD MM1 mice, revealing a progressive deregulation of inflammatory mediators with disease progression. Yet, inflammatory molecules involved are subjected to species differences in humans and mice. Moreover, inflammatory-related cell signaling pathways NFκB/IKK and JAK/STAT are activated in sCJD and sCJD MM1 mice. Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD. Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD.

No MeSH data available.


Related in: MedlinePlus