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Mouse neuronal CAD 5 cell line effectively propagates various strains of prions. Previously, we have shown that it can also be differentiated into the cells morphologically resembling neurons. Here, we demonstrate that CAD 5 cells chronically infected with prions undergo differentiation under the same conditions. To make our model more realistic, we triggered the differentiation in the 3D culture created by gentle rocking of CAD 5 cell suspension. Spheroids formed within 1 week and were fully developed in less than 3 weeks of culture. The mature spheroids had a median size of ~300 μm and could be cultured for up to 12 weeks. Increased expression of differentiation markers GAP 43, tyrosine hydroxylase, β‐III‐tubulin and SNAP 25 supported the differentiated status of the spheroid cells. The majority of them were found in the G0/G1 phase of the cell cycle, which is typical for differentiated cells. Moreover, half of the PrPC on the cell membrane was N‐terminally truncated, similarly as in differentiated CAD 5 adherent cells. Finally, we demonstrated that spheroids could be created from prion‐infected CAD 5 cells. The presence of prions was verified by immunohistochemistry, western blot and seed amplification assay. We also confirmed that the spheroids can be infected with the prions de novo. Our 3D culture model of differentiated CAD 5 cells is low cost, easy to produce and cultivable for weeks. We foresee its possible use in the testing of anti‐prion compounds and future studies of prion formation dynamics. [ABSTRACT FROM AUTHOR]

Prion diseases are incurable, infectious and fatal neurodegenerative diseases that affect both humans and animals. The pathogenesis of prion disease involves the misfolding of the cellular prion protein, PrPC, to a disease-causing conformation, PrPSc, in the brain. The exact mechanism of conversion of PrPC to PrPSc is not clear; however, there are numerous studies supporting that this process of misfolding requires the association of PrPC with lipid raft domains of the plasma membrane. An increase in the cellular cholesterol content with prion infection has been observed in both in vivo and in vitro studies. As cholesterol is critical for the formation of lipid rafts, on the one hand, this increase may be related to, or aiding in, the process of prion conversion. On the other hand, increased cholesterol levels may affect neuronal viability. Here, we discuss current literature on the underlying mechanisms and potential consequences of elevated neuronal cholesterol in prion infection and advancements in prion disease therapeutics targeting brain cholesterol homeostasis. [ABSTRACT FROM AUTHOR]

Activation and proliferation of microglia are one of the hallmarks of prion disease and is usually accompanied by increased levels of various cytokines and chemokines. Our previous study demonstrated that the level of brain macrophage colony-stimulating factor (M-CSF) was abnormally elevated during prion infection, but its association with PrPSc is not completely clear. In this study, colocalization of the increased M-CSF with accumulated PrPSc was observed by IHC with serial brain sections. Reliable molecular interaction between total PrP and M-CSF was observed in the brain of 263 K-infected hamsters and in cultured prion-infected cell line. Immunofluorescent assays showed that morphological colocalization of M-CSF with neurons and microglia, but not with astrocytes in brains of scrapie-infected animals. The transcriptional and expressing levels of CSF1R were also significantly increased in prion-infected cell line and mice, and colocalization of CSF1R with neurons and microglia was observed in the brains of prion-infected mouse models. Removal of PrPSc replication by resveratrol in SMB-S15 cells induced limited reductions of cellular levels of M-CSF and CSF1R. In addition, we found that the level of IL-34, another ligand of CSF1R, did not change significantly after prion infection, but its distribution on the cell types in the brains shifted from neurons in healthy mice to the proliferated astrocytes and microglia in scrapie-infected mice. Our data demonstrate activation of M-CSF/IL-34/CSF1R signaling in the microenvironment of prion infection, strongly indicating its vital role in the pathophysiology of prions. It provides solid scientific evidence for the therapeutic potential of inhibiting M-CSF/CSF1R signaling in prion diseases. [ABSTRACT FROM AUTHOR]

Evidence of the gut microbiota influencing neurodegenerative diseases has been reported for several neural diseases. However, there is little insight regarding the relationship between the gut microbiota and prion disease. Here, using fecal samples of 12 prion-infected mice and 25 healthy controls, we analyzed the structure of the gut microbiota and metabolic changes by 16S rRNA sequencing and LC-MS–based metabolomics respectively as multi-omic analyses. Additionally, SCFAs and common amino acids were detected by GC–MS and UPLC respectively. Enteric changes induced by prion disease affected both structure and abundances of the gut microbiota. The gut microbiota of infected mice displayed greater numbers of Proteobacteria and less Saccharibacteria at the phylum level and more Lactobacillaceae and Helicobacteraceae and less Prevotellaceae and Ruminococcaceae at the family level. A total of 145 fecal metabolites were found to be significantly different in prion infection, and most (114) of these were lipid metabolites. Using KEGG pathway enrichment analysis, we found that 3 phosphatidylcholine (PC) compounds significantly decreased and 4 hydrophobic bile acids significantly increased. Decreases of 8 types of short-chain acids (SCFAs) and increases of Cys and Tyr and decreases of His, Trp, and Arg were observed in prion infection. Correlation analysis indicated that the gut microbiota changes observed in our study may have been the shared outcome of prion disease. These findings suggest that prion disease can cause significant shifts in the gut microbiota. Certain bacterial taxa can then respond to the resulting change to the enteric environment by causing dramatic shifts in metabolite levels. Our data highlight the health impact of the gut microbiota and related metabolites in prion disease.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrPSc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway. [ABSTRACT FROM AUTHOR]

Unlike other species, prion disease has never been described in dogs even though they were similarly exposed to the bovine spongiform encephalopathy (BSE) agent. This resistance prompted a thorough analysis of the canine PRNP gene and the presence of a negatively charged amino acid residue in position 163 was readily identified as potentially fundamental as it differed from all known susceptible species. In the present study, the first transgenic mouse model expressing dog prion protein (PrP) was generated and challenged intracerebrally with a panel of prion isolates, none of which could infect them. The brains of these mice were subjected to in vitro prion amplification and failed to find even minimal amounts of misfolded prions providing definitive experimental evidence that dogs are resistant to prion disease. Subsequently, a second transgenic model was generated in which aspartic acid in position 163 was substituted for asparagine (the most common in prion susceptible species) resulting in susceptibility to BSE‐derived isolates. These findings strongly support the hypothesis that the amino acid residue at position 163 of canine cellular prion protein (PrPC) is a major determinant of the exceptional resistance of the canidae family to prion infection and establish this as a promising therapeutic target for prion diseases. [ABSTRACT FROM AUTHOR]

Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in an ex vivo model was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, in in vivo and ex vivo prion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases. [ABSTRACT FROM AUTHOR]

Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrPC molecules are converted into abnormally folded scrapie isoforms termed PrPSc. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrPC as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrPC into PrPSc in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrPC. We further show that both prion infection and PrPC depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrPC-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

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 PrPC to PrPSc 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. [ABSTRACT FROM AUTHOR]

Literature data on the role of physiological prion in Ca2+-homeostasis regulation, violation promoting prion-induced neurodegenerations, are summarized. The electrophysiological neuronal disorders and synaptic dysfunction which occur during prion di­seases and are accompanied by changes in intracellular ionized Ca2+ concentration, are described. Short description of Ca2+-transport systems in neurons is presented. Special attention is paid to data obtained in animal models of prion infections and PrP-knocked animals, indicating possible role of PrPc in the process of Ca2+-transport in neurons. In particular, a PrPc mediated participation in functioning of calcium channels due to binding with NR2D-subunit of N-methyl-D-aspartate (NMDA)-receptors of Ca2+-channels, which provides its neuroprotective role, is described. Also, a PrPc participation in the synaptic structure formation and neurotransmission is characterized. The interaction of physiological prion with synapsin-1 and synaptophysin that regulates exo-endoendocytosis synaptic vesicles cycle, was studied. The violation of Ca2+-homeostasis as one of important factors during prion pathologies is characterised.

The cellular prion protein PrPC was initially discovered as the normal counterpart of the pathological scrapie prion protein PrPSc, the main component of the infectious agent of Transmissible Spongiform Encephalopathies. While clues as to the physiological function of this ubiquitous protein were greatly anticipated from the development of knock-out animals, PrP-null mice turned out to be viable and to develop without major phenotypic abnormalities. Notwithstanding, the discovery that hematopoietic stem cells from PrP-null mice have impaired long-term repopulating potential has set the stage for investigating into the role of PrPC in stem cell biology. A wealth of data have now exemplified that PrPC is expressed in distinct types of stem cells and regulates their self-renewal as well as their differentiation potential. A role for PrPC in the fate restriction of embryonic stem cells has further been proposed. Paralleling these observations, an overexpression of PrPC has been documented in various types of tumours. In line with the contribution of PrPC to stemness and to the proliferation of cancer cells, PrPC was recently found to be enriched in subpopulations of tumour-initiating cells. In the present review, we summarize the current knowledge of the role played by PrPC in stem cell biology and discuss how the subversion of its function may contribute to cancer progression.

The cellular prion protein PrPC is the normal counterpart of the scrapie prion protein PrPSc, the main component of the infectious agent of Transmissible Spongiform Encephalopathies. The recent discovery that PrPC can serve as a receptor for the amyloid Αβ peptide and relay its neurotoxicity is sparking renewed interest on this protein and its involvement in signal transduction processes. Disease-associated PrPSc shares with Αβ the ability to hijack PrPC-dependent signalling cascades, and thereby instigate pathogenic events. Among these is an impairment of Αβ clearance, uncovered in prion-infected neuronal cells. These findings add another facet to the intricate interplay between PrPC and Αβ. Here, we summarize the connection between PrP-mediated signalling and Αβ clearance and discuss its pathological implications.

The cellular prion protein PrPc is the normal counterpart of the scrapie prion protein PrPSc, the main component of the infectious agent of transmissible spongiform encephalopathies. The recent discovery that PrPc can serve as a receptor for the amyloid beta (Aβ) peptide and relay its neurotoxicity is sparking renewed interest on this protein and its involvement in signal transduction processes. Disease-associated PrPSc shares with Aβ the ability to hijack PrPc-dependent signaling cascades, and thereby instigate pathogenic events. Among these is an impairment of Aβ clearance, uncovered in prion-infected neuronal cells. These findings add another facet to the intricate interplay between PrPc and Aβ. Here, we summarize the connection between PrP-mediated signaling and Aβ clearance and discuss its pathological implications. [ABSTRACT FROM AUTHOR]

Background Rhesus monkeys were used as a non-human primate model to study small non-coding RNA after infection with human sporadic and variant Creutzfeldt-Jakob prions. Methods Tissue-specific Alu DNA element transcription and editing of transcripts were assessed in neuronal - and blood cells (Buffy Coat). Results Tissue/cell-specific transcription and editing patterns were obtained. Active Alu DNA elements belonged to several Alu DNA families, they could be located on several chromosomes, and their genomic sites were identified. Deamination by adenosine deaminase acting on RNA and apolipoprotein B editing complex was found. Conclusions Different Alu transcription and editing programmes exist and may depend on the infection status. [ABSTRACT FROM AUTHOR]

Gastric juice is a unique combination of hydrochloric acid and the proteolytic enzyme pepsin. Its main function is to inactivate ingested microorganisms. Prions cause fatal transmissible degenerative encephalopathies in animals and man. These diseases have attracted attention due to the proposed link between bovine spongiform encephalopathy in cattle and the occurrence of a new variant Creutzfeldt-Jakob disease in humans where the most probable route of transmission is via contaminated food. The role of gastric juice in the protection against these agents is not settled. Objective. The aim of this study was to examine if drug-induced gastric hypoacidity increases the susceptibility of prion infection transmitted by the oral route. Material and methods. Forty-six mice (tg338) were given brain homogenates contaminated with scrapie by gastric intubation. Twenty-two of these animals were concomitantly dosed with omeprazole increasing the median gastric pH from 1.2 to 5.3. After 381 days, the animals were sacrificed and all the brains were examined for detection of pathogenic prion proteins by enzyme-linked immunosorbent assay and western blot. Results. Drug-induced decrease in gastric acidity more than doubled the rate (59% vs. 25%, p < 0.035) of brain infection compared to controls with normal gastric acidity at the time of inoculation. Conclusions. Our results demonstrate that the normal gastric juice constitutes a significant defense against prion disease in mice. Thus, gastric hypochlorhydria would be expected to enhance the susceptibility to prion infection by the oral route. This finding may have relevance to the pathogenesis of the new variant Creutzfeldt-Jakob disease and prion diseases in general. [ABSTRACT FROM AUTHOR]

Abstract: The sporadic and familial forms of Creutzfeldt-Jacob disease (sCJD and fCJD) usually appear at older ages (60–70 years and ∼50, respectively). Nevertheless, infectious forms such as Kuru and variant CJD (vCJD) present mostly at a much earlier age. To study the effect of age on the pathogenesis of infectious prion disease, we inoculated young and aged mice intraperitoneally with RML prions, followed them to disease end point and studied their disease characteristics. We now show that mice infected at older age present a significantly longer incubation time then mice infected at young age. Additionally, brains of mice infected at older age present significantly less disease-specific pathological markers such as gliosis, vacuolation and PrPSc accumulation. Concomitantly, gene expression analysis revealed that the upregulation of disease-associated inflammatory and stress-response genes, was significantly less pronounced in the brains of mice infected at older age. Based on this data, we suggest that alterations associated with aging, are accountable for the delay in the disease onset and the milder pathology in prion-infected aged mice. [Copyright &y& Elsevier]

Lithium is used for several decades to treat manic-depressive illness (bipolar affective disorder). Recently, it was found that lithium induces autophagy, thereby promoting the clearance of mutant huntingtin and α-synucleins in experimental systems. We show here for the first time that lithium significantly reduces the amount of pathological prion protein (PrPSc) in prion-infected neuronal and non-neuronal cultured cells by inducing autophagy. Treatment of prion-infected cells with 3-methyladenine, a potent inhibitor of autophagy, counteracted the anti-prion effect of lithium, demonstrating that induction of autophagy mediates degradation of PrPSc. Co-treatment with lithium and rapamycin, a drug widely used to induce autophagy, had an additive effect on PrPSc clearance compared to treatment with either drug alone. In addition, we provide evidence that the ability to reduce PrPSc and to induce autophagy is common for diverse lithium compounds, not only for the drug lithium chloride, usually administered in clinical therapy. Furthermore, we show here that besides reduction of PrPSc-aggregates, lithium-induced autophagy also slightly reduces the levels of cellular prion protein. Limiting the substrate available for conversion of cellular prion protein into PrPSc may provide an additional mechanism for reduction of PrPSc by lithium-induced autophagy. [ABSTRACT FROM AUTHOR]

The cellular prion protein (PrPc) is a glycosyl-phosphatidylinositol (GPI)-anchored protein trafficking in the secretory and endocytic pathway and localized mainly at the plasma membrane. Conversion of PrPc into its pathogenic isoform PrPSc is associated with pathogenesis and transmission of prion diseases. Intramolecular cleavage in the middle, the extreme C-terminal part or within the GPI anchor and shedding of PrPc modulate this conversion process by reducing the substrate for prion formation. These phenomena provide similarities with the processing of amyloid precursor protein in Alzheimer’s disease. Sorting nexins are a family of proteins with important functions in protein trafficking. In this study, we investigated the role of the newly described sorting nexin 33 (SNX33) in trafficking and processing of PrPc. We found that overexpression of SNX33 in neuronal and non-neuronal cell lines resulted in increased shedding of full-length PrPc from the plasma membrane and modulated the rate of PrPc endocytosis. This was paralleled by reduction of PrPSc formation in persistently and newly infected cells. Using deletion mutants, we demonstrate that production of PrP fragment N1 is not influenced by SNX33. Our data provide new insights into the cellular mechanisms of PrPc shedding and show how this can affect cellular PrPSc conversion. [ABSTRACT FROM AUTHOR]

Abstract: Transmissible spongiform encephalopaties (TSEs) or prion diseases develop as central nervous system (CNS) disorders characterized by extremely long incubation periods. Although TSEs do not go along with inflammatory infiltrates and/or antibody production against the prion protein (PrPSc), the immune system plays an important role in pathogenesis as long as different lymphoid organs (Peyer''s patches, lymph nodes and spleen) may facilitate the accumulation and further spread of prions after peripheral exposure. In this work we investigated the changes in lymphoid and dendritic cell (DC) populations as well as the implications of different cytokines during disease progression after experimental oral inoculation of prions in a transgenic mouse model. At different days post-inoculation (dpi), T and B lymphocytes and DC populations from lymphoid organs, blood and brain were analyzed by flow cytometry and immunohistochemistry. Besides time related variations in lymphoid cell numbers due to the aging of the animals significant changes related with the infection were found in mesenteric lymph nodes, peripheral blood leukocytes (PBLs) as well as in spleen, affecting the CD4/CD8 ratio. In contrast, little or no variation was detected in Peyer''s Patches or in thymus either associated with aging or the infection status. At individual time points significant differences between infected and control mice were seen in the CD8, CD4 and DC populations, with less evidence of differences in the B cell compartment. Finally, a pro-inflammatory phenotype occurred at early times in the spleen, where the levels of lymphotoxin-β mRNA were found augmented with respect to controls. Altogether, these results suggest that normal regulation of lymphocyte populations becomes altered along the progression of a prion infection. [Copyright &y& Elsevier]

Abstract: Prion infections induce severe disruption of the central nervous system with neuronal vacuolation and extensive glial reactions, and invariably lead to death of affected individuals. The molecular underpinnings of these events are not well understood. To better define the molecular consequences of prion infections, we analyzed the transcriptional response to persistent prion infection in a panel of three murine neural cell lines in vitro. Colony spot immunochemistry assays indicated that 65–100% of cells were infected in each line. Only the Nav1 gene was marginally modulated in one cell line, whereas transcripts previously reported to be derailed in prion-infected cells were not confirmed in the present study. We attribute these discrepancies to the experimental stringency of the current study, which was performed under conditions designed to minimize potential genetic drifts. These findings are at striking variance with gene expression studies performed on whole brains upon prion infections in vivo, suggesting that many of the latter changes represent secondary reactions to infection. We conclude that, suprisingly, there are no universal transcriptional changes induced by prion infection of neural cells in vitro. [Copyright &y& Elsevier]

The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under endoplasmic reticulum (ER) stress conditions. X-box-binding protein-1 (XBP-1) is a key transcriptional regulator of the UPR that activates genes involved in protein folding, secretion, and degradation to restore ER function. The occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation. However, the role of the UPR in the CNS has not been addressed directly. Here we describe the generation of a brain-specific XBP-1 conditional KO strain (XBP-1Nes-/-). XBP-1Nes-/- mice are viable and do not develop any spontaneous neurological dysfunction, although ER stress signaling in XBP-1Nes-/- primary neuronal cell cultures was impaired. To assess the function of XBP-1 in pathological conditions involving protein misfolding and ER stress, we infected XBP-1Nes-/- mice with murine prions. To our surprise, the activation of stress responses triggered by prion replication was not influenced by XBP-1 deficiency. Neither prion aggregation, neuronal loss, nor animal survival was affected. Hence, this most highly conserved arm of the UPR may not contribute to the occurrence or pathology of neuro-degenerative conditions associated with prion protein misfolding despite predictions that such diseases are related to ER stress and irreversible neuronal damage. [ABSTRACT FROM AUTHOR]

Foodborne transmission of bovine spongiform encephalopathyencephalopathy (BSE) to humans as variant Creutzfeldt-Jakob disease (CJD) has affected over 100 individuals, and probably millions of others have been exposed to BSE-contaminated food substances. Despite these obvious public health concerns, surprisingly little is known about the mechanism by which PrP-scrapie (PrpSc), the most reliable surrogate marker of infection in BSE-contaminated food, crosses the human intestinal epithelial cell barrier. Here we show that digestive enzyme (DE) treatment of sporadic CJD brain homogenate generates a C-terminal fragment similar to the proteinase K-resistant PrPSc core of 27-30 kDa implicated in prion disease transmission and pathogenesis. Notably, DE treatment results in a PrP Sc-protein complex that is avidly transcytosed in vesicular structures across an in vitro model of the human intestinal epithelial cell barrier, regardless of the amount of endogenous PrPC expression. Unexpectedly, PrPSc is cotransported with ferritin, a prominent component of the DE-treated PrP Sc-protein complex. The transport of PrPSc-ferritin is sensitive to low temperature, brefeldin-A, and nocodazole treatment and is inhibited by excess free ferritin, implicating a receptor- or transporter-mediated pathway. Because ferritin shares considerable homology across species, these data suggest that PrP Sc-associated proteins, in particular ferritin, may facilitate PrP Sc uptake in the intestine from distant species, leading to a carrier state in humans. [ABSTRACT FROM AUTHOR]

Background: The transmissible degenerative encephalopathies (TDEs) constitute a distinct group of diseases (scrapie in sheep, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD) in humans). The causal agents are not fully characterized, but are known to be resistant to most inactivation procedures. Ruminants appear to be particularly susceptible to TDEs. The concentrations of hydrochloric acid in their digestive tracts are significantly lower than in monogastric species. Methods: The aim of the study was to examine the role of gastric acidity in the protection of mice against infection after intragastric administration of different doses of a scrapie agent. Gastric acidity levels in mice were reduced by adding ranitidine to the drinking water and the animals were observed for neurological symptoms and at sacrifice examined microscopically for spongiform lesions in the brain. Results: The lower doses of infectious material induced disease significantly more often in mice given ranitidine compared with the controls. Conclusion: These data indicate that the normal levels of gastric acidity in mice protect them to some extent from infection with low doses of scrapie agent. This finding is potentially relevant to the pathogenesis of the variant form of CJD, which appears to be associated with the consumption of BSE-infected food products. [ABSTRACT FROM AUTHOR]