Brain microglia were activated in sporadic CJD but almost unchanged in fatal familial insomnia and G114V genetic CJD

Abstract

BackgroundMicroglial activations have been described in different subtypes of human prion diseases such as sporadic Creutzfeldt-Jakob disease (CJD), variant CJD, Kuru and Gerstmann-Sträussler-Scheinker disease (GSS). However, the situation of microglia in other genetic prion diseases such as fatal familial insomnia (FFI) and familial CJD remains less understood. The brain microglia was evaluated comparatively between the FFI, G114V and sCJD cases in the study.MethodsSpecific Western blots, immunohistochemical and immunofluorescent assays were used to detect the changes of microglia and ELISA tests were used for levels of inflammatory cytokines.ResultsWestern blots, immunohistochemical and immunofluorescent assays illustrated almost unchanged microglia in the temporal lobes of FFI and G114V gCJD, but obviously increased in those of sCJD. The Iba1-levels maintained comparable in six different brain regions of FFI and G114V cases, including thalamus, cingulate gyrus, frontal cortex, parietal cortex, occipital cortex and temporal cortex. ELISA tests for inflammatory cytokines revealed significantly up-regulated IL-1β, IL-6 and TNF-α in the brain homogenates from sCJD, but not in those from FFI and G114V gCJD.ConclusionData here demonstrates silent brain microglia in FFI and G114V gCJD but obviously increased in sCJD, which reflects various pathogenesis of different human prion diseases subtypes.

Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt–Jakob Disease

“…In addition, CJD brains have high levels of several inflammatory 99 cytokines, including IL-1 (Sharief et al, 1999;Shi et al, 2013;Llorens et al, 2014). However, it is not clear 100 which cell population is responsible for the increase in IL-1 , and whether this proinflammatory cytokine 101 contributes to enhancing NMDAR-mediated glutamatergic transmission (Viviani et al, 2003;Balosso et al, 102 2008), lowering the threshold for seizures (Vezzani and Viviani, 2015).…”

“…There is evidence 285 that interleukin-1 (IL-1 ) promotes Src family kinase (SFK)-mediated Tyr1472 phosphorylation of GluN2B 286 (Viviani et al, 2003), and its brain levels are high in CJD (Sharief et al, 1999;Shi et al, 2013;Llorens et al, …”

“…tissue levels in variant and sporadic CJD and in CJD-infected mice (Kordek et al, 1996;Sharief et al, 1999; 394 Shi et al, 2013;Llorens et al, 2014). …”

Microglia in prion diseases

“…Interestingly, microglial activation may vary between different human prion disease subtypes, since Western blots and immunohistochemical assays have demonstrated unaltered microglia in fatal familiar insomnia and genetic Creutzfeldt-Jakob disease (G114V) patients (30).…”

Distinct microglia profile in Creutzfeldt–Jakob disease and Alzheimer's disease is independent of disease kinetics

“…The majority of patients die within 1 year following onset of symptoms. The most common human prion disorder is sporadic Creutzfeldt–Jakob disease (sCJD) . Diagnostic procedures include neurological assessment, special magnetic resonance imaging (MRI) techniques such as fluid‐attenuated inversion recovery (FLAIR) and diffusion‐weighted imaging (DWI) and cerebrospinal fluid (CSF) protein analyses (measurement of 14‐3‐3 protein levels and real‐time quacking‐induced conversion assay, RT‐QuIC) .…”