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.
Highlights
Creutzfeldt–Jakob disease (CJD) is a fatal, transmissible spongiform encephalopathy (TSE) characterized by rapidly progressive dementia, pyramidal symptoms, myoclonus, ataxia, and akinetic mutism (Appleby et al, 2009)
The relationship between PrP deposition and neuroinflammation is obscure as reactive glia and associated cytokine expression are found in close vicinity to PrPSc deposits (Williams et al, 1997; Muhleisen et al, 1995; Guiroy et al, 1994), but microglial activation has been reported in regions of synaptic loss rather than in areas of PrPSc deposition (Cunningham et al, 2003)
REGIONAL AND SUBTYPE-SPECIFIC RESPONSES OF INFLAMMATORY MEDIATORS IN sporadic Creutzfeldt–Jakob disease (sCJD) BRAIN The astroglial activator LIF, the astroglial marker GFAP, the microglial markers CD11b and IBA1, and the activated microglial marker CD68 were up-regulated in sCJD cases, with increased expression levels in the frontal cortex in MM1 and in the cerebellum in VV2 cases (Figure 1)
Summary
Creutzfeldt–Jakob disease (CJD) is a fatal, transmissible spongiform encephalopathy (TSE) characterized by rapidly progressive dementia, pyramidal symptoms, myoclonus, ataxia, and akinetic mutism (Appleby et al, 2009). SCJD is a heterogeneous disease and the clinicopathological manifestations depend on its subtype as defined by PRNP codon 129 (Met/Met, Met/Val, or Val/Val) and PrPSc type (type 1 or type 2) This gives rise to six main sCJD subtypes, with MM1 and VV2 being the most common (Parchi et al, 1999; Parchi et al, 2009), and each one manifested by particular clinical and neuropathological traits (Parchi et al, 2012). Gliosis and cytokine overexpression seem to correlate with the severity of the neuropathological lesions (Van et al, 2002), and scrapie-infected models with regulated expression of cytokines lead to significant variations of prion incubation periods and to modifications of the timing of the appearance of clinical symptoms
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