23 research outputs found
Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie
Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie
Transmissible spongiform encephalopathies display long incubation periods at the beginning of which the titer of infectious agents (prions) increases in peripheral lymphoid organs. This “replication” leads to a progressive invasion of the CNS. Follicular dendritic cells appear to support prion replication in lymphoid follicles. However, the subsequent steps of neuroinvasion remain obscure. CD11c(+) dendritic cells, an unrelated cell type, are candidate vectors for prion propagation. We found a high infectivity titer in splenic dendritic cells from prion-infected mice, suggesting that dendritic cells carry infection. To test this hypothesis, we injected RAG-1(0/0) mice intravenously with live spleen cell subsets from scrapie-infected donors. Injection of infected dendritic cells induced scrapie without accumulation of prions in the spleen. These results suggest that CD11c(+) dendritic cells can propagate prions from the periphery to the CNS in the absence of any additional lymphoid element
Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a β-sheet breaker peptide
Genetic, neuropathological, and biochemical studies have provided strong evidence for a central role of amyloid in the pathogenesis of Alzheimer's disease (AD). We have proposed previously that peptides designed as beta-sheet breakers may be useful in preventing the formation of amyloid plaques. In this study, we describe a modified beta-sheet breaker peptide with improved pharmacological properties, a high rate of penetration across the blood-brain barrier, and the ability to induce a dramatic reduction in amyloid deposition in two different transgenic AD models. In addition, we report for the first time a significant increase in neuronal survival and a decrease in brain inflammation associated with the reduction of amyloid plaques. These results demonstrate that the process of amyloid deposition is one of the causes of neurodegeneration in AD. Moreover, our findings indicate that beta-sheet breaker peptides provide a valuable tool for evaluating further the importance of amyloid in the etiology of AD and suggest that these peptides or some of their derivatives might be good candidates for AD treatment
Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie
Identification of VHY/Dusp15 as a Regulator of Oligodendrocyte Differentiation through a Systematic Genomics Approach
<div><p>Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease. We have undertaken a systematic genomic approach to evaluate PTP gene activity in multiple sclerosis autopsies and in related <em>in vivo</em> and <em>in vitro</em> models of the disease. This effort led to the identification of Dusp15/VHY, a PTP previously believed to be expressed only in testis, as being transcriptionally regulated during OL differentiation and in MS lesions. Subsequent RNA interference studies revealed that Dusp15/VHY is a key regulator of OL differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation.</p> </div
Phosphatase activity of GST-tagged full length Dusp15/VHY.
<p>A. Dusp15 phosphatase activity was assessed using the DiFMUP (6,8-difluoro-4-methyumbelliferyl phosphate) assay at the experimentally optimal enzyme concentration of 4 ng/mL. B. Optimal pH activity (pH 6) was determined by testing a pH range from pH 3 to 8. C. and D. Activity of Dusp15/VHY on phospho-peptides substrates corresponding respectively to pY<sub>119</sub> and pY<sub>771</sub> dephosphorylation sites of SNX6 (NED(pY<sub>119</sub>)AGYIIPPAP) and PDGFR-β (IESSN(pY<sub>771</sub>)MAPYD). VHY/Dusp15 was used at 4 ng/mL at pH6 and activity was detected using the Malachite Green phosphate detection assay. OD, Optical Density at 620 nm. Dissociation constant (Km) was calculated as the substrate concentration needed to reach V<sub>max</sub>/2 and expressed as Mean ± S<sub>EM</sub> of three different experiments.</p
Correlation chart between MBP expression and dusp15 expression over a time course of differentiation in olineu.
<p>Values expressed as fold induction <i>versus</i> undifferentiated controls (starting cultures) and correspond to the Mean ± SD of two different experiments (n = 2). Dusp15/VHY expression increases with time and correlates with MBP expression during the first steps of Oli-neu differentiation then Dusp15 expression reaches a maximum at 15 h prior to the MBP expression peak occurring at 24 h.</p
Literature data for expression of selected PTPs in purified cells from rodent brain.
a<p>Data extracted from GEO dataset GSE9566: GSM241928 (56A); GSM241929 (61D); GSM241930 (69E); GSM241931 (72A); GSM241932 (79E); GSM241933 (80O); GSM241934 (80P); GSM241935 (80Q); GSM241936 (81A); GSM241937 (81B). Samples designations correspond to the one used by the cited authors. Cell types were purified from post-natal mouse forebrains using FACS analysis. For more details see <i>Cahoy et al</i>, 2007.</p>b<p>Data extracted from Geo dataset GDS2379: GSM138218-GSM138222 (n = 5); GSM138223-GSM138229 (n = 4). OL cell types were purified from post-natal P7 rats using FACS analysis. For more details see Nielsen <i>et al</i>, 2006.</p
Correlation chart between MBP expression and dusp15 expression over a time course of differentiation in mouse primary cortical cultures.
<p>Values expressed as fold induction <i>versus</i> DIV5 cultures and correspond to the Mean ± SD of two different experiments (n = 3). Dusp15/VHY expression increases with time and correlates with MBP expression until DIV12 then reaches a maximum whereas MBP expression still increases until DIV15.</p
Differential gene expression of PTP family members in MS white and gray matter lesions.
<p>Data were expressed as a <i>ratio</i> of % expression <i>vs</i> HKGs between two samples (fold change) and represented in a volcano plot diagram (y: <i>P</i>value; x: fold change). An intensive modulation is characterized by spread values close to the x axis (magnification in square). <i>NAWM</i>, Normal-appearing White Matter; <i>NAGM</i>, Normal-appearing Grey Matter; <i>WML</i>, White Matter Lesion; <i>GML</i>, Gray Matter Lesion; <i>CGM</i>, Control gray Matter; <i>CWM</i>, Control White Matter. Major changes occur in lesioned areas and are more intensive in white matter.</p