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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

Characterization of sCJD MM1 mice is shown. (A) PrPSc distribution in inoculated animals as revealed by Pet-blot analysis at end stages of the disease. Images show PrPSc labeling in the neocortex, entorhinal cortex, amygdala, hippocampus, and thalamus, and to a lesser degree striatum, cerebellum, and dorsal midbrain. (B) PrP expression in the cortex and cerebellum of inoculated animals as revealed by Western-blot analysis. Densitometry values of three animals/time point show a significant decrease in the expression of PrP at clinical stages in the cortex of sCJD MM1 mice.
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Figure 5: Characterization of sCJD MM1 mice is shown. (A) PrPSc distribution in inoculated animals as revealed by Pet-blot analysis at end stages of the disease. Images show PrPSc labeling in the neocortex, entorhinal cortex, amygdala, hippocampus, and thalamus, and to a lesser degree striatum, cerebellum, and dorsal midbrain. (B) PrP expression in the cortex and cerebellum of inoculated animals as revealed by Western-blot analysis. Densitometry values of three animals/time point show a significant decrease in the expression of PrP at clinical stages in the cortex of sCJD MM1 mice.

Mentions: In order to evaluate neuroinflammatory changes with disease progression, rather than changes due to MM1 or VV2 subtype, only sCJD MM1 and no sCJD VV2 animals were used for this purpose. PrPSc deposition was assessed using paraffin-embedded tissue blot (PET-Blot) in brain coronal sections at the level of the thalamus and in the cerebellum of MM1-inoculated mice at clinical stages. PrPSc deposition was observed in cerebral neocortex, entorhinal cortex, amygdala, hippocampus, thalamus, and, to a lesser degree, in striatum, cerebellum, and dorsal brain stem (Figure 5A). No PrPSc labeling was detected in control animals (data not shown). Total PrP levels decreased in the cortex of the MM1-inoculated mice in parallel to the appearance of clinical symptoms (160 dpi), and they remained steady until the final stages; total PrP cerebellar levels were not modified with disease progression (Figure 5B).


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)

Characterization of sCJD MM1 mice is shown. (A) PrPSc distribution in inoculated animals as revealed by Pet-blot analysis at end stages of the disease. Images show PrPSc labeling in the neocortex, entorhinal cortex, amygdala, hippocampus, and thalamus, and to a lesser degree striatum, cerebellum, and dorsal midbrain. (B) PrP expression in the cortex and cerebellum of inoculated animals as revealed by Western-blot analysis. Densitometry values of three animals/time point show a significant decrease in the expression of PrP at clinical stages in the cortex of sCJD MM1 mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Characterization of sCJD MM1 mice is shown. (A) PrPSc distribution in inoculated animals as revealed by Pet-blot analysis at end stages of the disease. Images show PrPSc labeling in the neocortex, entorhinal cortex, amygdala, hippocampus, and thalamus, and to a lesser degree striatum, cerebellum, and dorsal midbrain. (B) PrP expression in the cortex and cerebellum of inoculated animals as revealed by Western-blot analysis. Densitometry values of three animals/time point show a significant decrease in the expression of PrP at clinical stages in the cortex of sCJD MM1 mice.
Mentions: In order to evaluate neuroinflammatory changes with disease progression, rather than changes due to MM1 or VV2 subtype, only sCJD MM1 and no sCJD VV2 animals were used for this purpose. PrPSc deposition was assessed using paraffin-embedded tissue blot (PET-Blot) in brain coronal sections at the level of the thalamus and in the cerebellum of MM1-inoculated mice at clinical stages. PrPSc deposition was observed in cerebral neocortex, entorhinal cortex, amygdala, hippocampus, thalamus, and, to a lesser degree, in striatum, cerebellum, and dorsal brain stem (Figure 5A). No PrPSc labeling was detected in control animals (data not shown). Total PrP levels decreased in the cortex of the MM1-inoculated mice in parallel to the appearance of clinical symptoms (160 dpi), and they remained steady until the final stages; total PrP cerebellar levels were not modified with disease progression (Figure 5B).

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