Neuroinflammation has been correlated with the progress of neurodegeneration in many neuropathologies. Although glial cells have traditionally been considered to be protective, the concept of them as neurotoxic cells has recently emerged. Thus, a major unsolved question is the exact role of astroglia and microglia in neurodegenerative disorders. On the other hand, it is well known that glucocorticoids are the first choice to regulate inflammation and, consequently, neuroglial inflammatory activity. The objective of this study was to determine how chronic dexamethasone treatment influences the host immune response and to characterize the beneficial or detrimental role of glial cells. To date, this has not been examined using a natural neurodegenerative model of scrapie. With this aim, immunohistochemical expression of glial markers, prion protein accumulation, histopathological lesions and clinical evolution were compared with those in a control group. The results demonstrated how the complex interaction between glial populations failed to compensate for brain damage in natural conditions, emphasizing the need for using natural models. Additionally, the data showed that modulation of neuroinflammation by anti-inflammatory drugs might become a research focus as a potential therapeutic target for prion diseases, similar to that considered previously for other neurodegenerative disorders classified as prion-like diseases.

While prion diseases have been described in numerous species, some, including those of the Canidae family, appear to show resistance or reduced susceptibility. A better understanding of the factors underlying prion susceptibility is crucial for the development of effective treatment and control measures. We recently demonstrated resistance to prion infection in mice overexpressing a mutated prion protein (PrP) carrying a specific amino acid substitution characteristic of canids. Here, we show that coexpression of this mutated PrP and wild-type mouse PrP in transgenic mice inoculated with different mouse-adapted prion strains (22 L, ME7, RML, and 301C) significantly increases survival times (by 45 to 113%). These data indicate that this amino acid substitution confers a dominant-negative effect on PrP, attenuating the conversion of PrP to PrP and delaying disease onset without altering the neuropathological properties of the prion strains. Taken together, these findings have important implications for the development of new treatment approaches for prion diseases based on dominant-negative proteins.

The analysis of the cerebrospinal fluid (CSF) biomarkers in patients with suspected prion diseases became a useful tool in diagnostic routine. Prion diseases can only be identified at clinical stages when the disease already spread throughout the brain and massive neuronal damage occurs. Consequently, the accuracy of CSF tests detecting non-symptomatic patients is unknown. Here, we aimed to investigate the usefulness of CSF-based diagnostic tests in pre-clinical and clinical naturally occurring scrapie. While decreased total prion protein (PrP) levels and positive PrP seeding activity were already detectable at pre-symptomatic stages, the surrogate markers of neuronal damage total tau (tau) and 14-3-3 proteins were exclusively increased at clinical stages. The present findings confirm that alterations in PrP levels and conformation are primary events in the pathology of prion diseases preceding neuronal damage. Our work also supports the potential use of these tests in the screening of pre-symptomatic scrapie and human prion disease cases.

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phenotypic variability in prion diseases, such as scrapie, is associated to the existence of prion strains, which are different pathogenic prion protein (PrP Sc) conformations with distinct pathobiological properties. to faithfully study scrapie strain variability in natural sheep isolates, transgenic mice expressing sheep cellular prion protein (PrP c) are used. in this study, we used two of such models to bioassay 20 scrapie isolates from the Spain-France-Andorra transboundary territory. Animals were intracerebrally inoculated and survival periods, proteinase K-resistant PrP (PrP res) banding patterns, lesion profiles and PrP Sc distribution were studied. inocula showed a remarkable homogeneity on banding patterns, all of them but one showing 19-kDa PrP res. However, a number of isolates caused accumulation of 21-kDa PrP res in TgShp XI. A different subgroup of isolates caused long survival periods and presence of 21-kDa PrP res in Tg338 mice. It seemed that one major 19-kDa prion isoform and two distinct 21-kDa variants coexisted in source inocula, and that they could be separated by bioassay in each transgenic model. The reason why each model favours a specific component of the mixture is unknown, although prp c expression level may play a role. our results indicate that coinfection with more than one substrain is more frequent than infection with a single component. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of rare, fatal and progressive neurodegenerative disorders that affect both animals and human beings. TSEs are caused by non-conventional etiologic agents called prions. According to the widely accepted prion hypothesis 1 , prions consist exclusively of a pathogenic protein conformer, termed PrP Sc , that derives from the physiological, host-encoded cellular prion protein (PrP C) 1-3 via a post-translational conformational change that is triggered by PrP Sc itself in a feedback manner 4. PrP Sc accumulates in nervous tissue 5 and through a yet unclarified mechanism gives rise to neuronal death, neuron loss and vacuolization 6,7 , together with astrogliosis, microgliosis 8-10 and other neuroinflammatory phenomena 11. This progressive degeneration of the central nervous system manifests as a set of neurological signs appearing after long incubation periods. Although, according to the protein-only model 1 , the agent responsible for these disorders lacks nucleic acids, the existence of several phenotypic variants has been proved for different TSEs. This was first described for scrapie when two different clinical syndromes were observed in scrapie-infected goats, which were reproducible by intracerebral inoculation 12. Prion variants associated to these different phenotypes were termed "strains", by analogy with other infectious agents. Further demonstration of the existence of scrapie strains was addressed by studies in wild type mice 13,14 , which also established a methodology to discriminate them according to survival periods and lesion profiles 15-17 .

Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt–Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.

The actual role of prion protein-induced glial activation and subsequent cytokine secretion during prion diseases is still incompletely understood. The overall aim of this study is to assess the effect of an anti-inflammatory treatment with dexamethasone on different cytokines released by neuroglial cells that are potentially related to neuroinflammation in natural scrapie. This study emphasizes the complex interactions existent among several pleiotropic neuromodulator peptides and provides a global approach to clarify neuroinflammatory processes in prion diseases. Additionally, an impairment of communication between microglial and astroglial populations mediated by cytokines, mainly IL-1, is suggested. The main novelty of this study is that it is the first one assessing in situ neuroinflammatory activity in relation to chronic anti-inflammatory therapy, gaining relevance because it is based on a natural model. The cytokine profile data would suggest the activation of some neurotoxicity-associated route. Consequently, targeting such a pathway might be a new approach to modify the damaging effects of neuroinflammation.

Cadmium and lead contents were determined in pork and duck liver pastes produced in Spain. The average concentration levels that were measured were 19 ng/g for cadmium and 578 ng/g for lead in pork liver pastes and 14 ng/g for cadmium and 157 ng/g for lead in duck liver pastes. The possible sources of these trace elements were investigated: product formulation, technological process and packaging. It has been observed that the contents of lead in pork liver pastes are higher than would be expected from the liver content alone, and that the main source of lead is the tin container.