Gray F, Chretien F, Adle-Biassette H, Dorandeu A, Ereau T, Delisle MB, Kopp N, Ironside JW, Vital C.
Laboratoire de Neuropathologie, Faculte de Medecine Paris-Ouest, Garches, France.
Neuronal loss is a salient feature of prion diseases; however, its causes and mechanisms are unclear The possibility that it could occur through an apoptotic process has been postulated and is consistent with the lack of inflammation in prion disorders as supported by experimental studies. In order to test this hypothesis in humans, we examined samples of frontal and temporal cerebral cortex, striatum, thalamus, and cerebellum from 16 patients who died from Creutzfeldt-Jakob disease. They included 5 sporadic cases, 5 familial, 3 iatrogenic, and 3 cases with the new variant. These were compared with age and sex matched controls. Using in situ end labelling, we identified apoptotic neurons in all the cases of Creutzfeldt-Jakob disease. A single labelled neuron was found in the eldest control. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. This supports the view that apoptosis of neurons is a feature of prion diseases and may contribute to the neuronal loss which is one of the main characteristics of these conditions. Neuronal apoptosis also correlated well with microglial activation, as demonstrated by the expression of major histocompatibility complex class II antigens, and axonal damage, as identified by beta-amyloid protein precursor immunostaining. In contrast, we found no obvious relationship between the topography and severity of neuronal apoptosis and the type, topography, and abundance of prion protein deposits as demonstrated by immunocytochemistry.
PMID:_10218627
Neuropathol Appl Neurobiol. 2003 Jun;29(3):262-72. Comparison of the neuropathological characteristics of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) in mice.
Brown DA, Bruce ME, Fraser JR.
Neuropathogenesis Unit, Institute for Animal Health, Edinburgh, UK. debbie.browbsrc.ac.uk
Bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) belong to a group of diseases called the transmissible spongiform encephalopathies (TSEs). Transmission studies in inbred mice (strain typing) provided overwhelming evidence that vCJD arose from BSE. In this study, we compare the patterns of neuropathology in a panel of three inbred mouse strains (RIII, C57BL and VM) and one cross (C57BL x VM) infected with either vCJD or BSE. For each mouse strain, patterns of abnormal prion protein (PrPres) deposition, astrocytosis and vacuolation were similar in the vCJD- and BSE-challenged mice. Prion protein (PrP)-positive plaques were prominent in the VM and C57BL x VM mice in addition to diffuse PrPres accumulation, whereas only diffuse PrPres labelling was observed in the RIII and C57BL mice. The hippocampus was targeted in all mouse strains, as was the cochlear nucleus in the medulla, both showing consistent severe vacuolation and heavy PrPres deposition. Although the targeting of PrPres was similar in the BSE- and vCJD-infected brains, the amount and intensity of PrPres observed in the brains treated with formic acid during fixation was reduced considerably. The distribution of astrocytosis was similar to the targeting of PrPres deposition in the brain, although some differences were observed in the hippocampi of mice challenged with vCJD. We conclude that there are no significant differences in the targeting of neuropathological changes observed in the BSE- and vCJD-infected mice, consistent with the previous evidence of a link between BSE and vCJD.
PMID:_12787323
J Immunol. 2003 Jun 15;170(12):6040-7. Immunologically induced, complement-dependent up-regulation of the prion protein in the mouse spleen: follicular dendritic cells versus capsule and trabeculae.
Lotscher M, Recher M, Hunziker L, Klein MA.
Institutes of. Experimental Immunology and Neuropathology, University Hospital of Zurich, Zurich, Switzerland. marius.loetschety.usz.ch
The expression of the prion protein (PrP) in the follicular dendritic cell network of germinal centers in the spleen is critical for the splenic propagation of the causative agent of prion diseases. However, a physiological role of the prion protein in the periphery remains elusive. To investigate the role and function of PrP expression in the lymphoid system we treated naive mice i.v. with preformed immune complexes or vesicular stomatitis virus. Immunohistochemistry and Western blot analysis of the spleen revealed that 8 days after immunization, immune complexes and vesicular stomatitis virus had both induced a strong increase of PrP expression in the follicular dendritic cell network. Remarkably, this up-regulation did not occur in mice that lack an early factor of the complement cascade, C1q, a component which has been shown previously to facilitate early prion pathogenesis. In addition to the variable PrP level in the germinal centers, we detected steady and abundant PrP expression in the splenic capsule and trabeculae, which are structural elements that have not been associated before with PrP localization. The abundant trabeculo-capsular PrP expression was also evident in spleens of Rag-1-deficient mice, which have been shown before to be incapable of prion expansion. We conclude that trabeculocapsular PrP is not sufficient for splenic prion propagation. Furthermore, our observations may provide important clues for a physiological function of the prion protein and allow a new view on the role of complement and PrP in peripheral prion pathogenesis.
PMID:_12794132
Cell Biochem Biophys. 2003;38(3):287-304. The cellular prion protein: biochemistry, topology, and physiologic functions.
Griffoni C, Toni M, Spisni E, Bianco M, Santi S, Riccio M, Tomasi V.
Department of Experimental Biology, University of Bologna, Bologna, Italy.
Studies on the transmission from man to animals of Creutzfeld-Jacob disease (CJD) led Prusiner to identify a proteinaceous infectious particle lacking nucleic acid, which was called prion. The identification of the infectious prion (PrPsc) then led to the discovery of the normal cellular counterpart (PrPc). One of the still enigmatic aspects regarding prion diseases is actually how, where, and when the transformation PrPc/PrPsc is occurring, this being due to the result of a large extent to the fact that so far most studies have been dedicated to the formation and transmission of PrPsc, whereas the understanding of physiologic roles of PrPc are in their infancy. In this review, we hope to identify the most reliable hypotheses for future experiments on PrPc. This is relevant not only for the understanding of PrPc functions but also to unravel the enigmatic nature of PrPc/PrPsc conversion.
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