Subtype and Regional-Specific Neuroinflammation in Sporadic Creutzfeldt–Jakob Disease

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.

Cerebrospinal fluid markers in the differentiation of molecular subtypes of sporadic Creutzfeldt−Jakob disease

“…Recent studies revealed the distinct subtypes 0 neuropathology being the possible explanation for elevated CSF markers [20,21]. The regional specific manner of inflammatory markers between the VV1 and VV2 subtype might contribute to the different S100B CSF profile [22]. The time of sampling influenced the CSF protein levels rising in later stages of disease especially for tau, NSE and S100B (Table 3).…”

Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Correlation of Histopathology and MRI in Prion Disease

“…There is also evidence for microglial activation and neuroinflammation with increased expression of microglial markers in CJD 26–28 . In addition, Llorens et al has found that there is regional variation in microglia activation depending on molecular subtype in sporadic CJD 29 . An alternative explanation for limbic and mesolimbic hypermetabolism was considered because hypermetabolism has been reported in other neurological disorders, such as limbic encephalitis 30 .…”

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models

“…It is known that marked modification of the profile of gene expression of cytokines and molecules linked with the inflammatory response occurs in the cerebral cortex and other brain regions of mice with age. This happens in normal aging and also in transgenic mice including APP/PS1, P301S-MAPT and S49P-Syracuse human neuroserpin (S49P-Syracuse), and in CJD-induced prionopathy in murine PrP-null mice expressing human PrP, which are models of human β-amyloidopathy reminiscent of Alzheimer disease, familial frontotemporal degeneration-tauopathy (FTLD-tau), neuroserpinopathy and Creutzfeldt-Jakob disease, respectively [33–36]. This pattern is repeated in our study as C3ar1 , C4b , Csf3r , Tlr4 , Ccl4, Ccl6 , CxCl10 , Il1b, Il6 , Tnfα, Il10ra and Il10rb mRNA expression levels increase and C1ql1 levels significantly decrease in WT, Epm2a −/− and Epm2b −/− mice aged 12 months when compared with mice aged 16 days.…”