Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic Pathway

Trifilo, Matthew J.; Sanchez‐Alavez, Manuel; Solforosi, Laura; Bernard‐Trifilo, Joie A.; Kunz, Stefan; McGavern, Dorian B.; Oldstone, Michael B. A.

doi:10.1128/jvi.00486-08

Cited by 14 publications

(16 citation statements)

References 36 publications

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“…PrPsc conversion from PrPc was not detected in the thymus of these mice. As Figure 1 illustrates, the PrPsc was mono-glycosylated (by Western blot) which corresponded to our early observations with brain and heart (Chesebro et al, 2005; Trifilo et al, 2008; Trifilo et al, 2006). None of the tissues obtained from uninfected GPI −/− PrP tg mice displayed PrPsc by either Western blot or immunohistochemistry (data not shown).…”

Section: Resultssupporting

confidence: 85%

“…However, despite abundant deposits of the abnormally folded PrPsc that quantitatively and significantly exceeded PrPsc deposits formed in scrapie-infected mice with a membrane anchored PrP, these scrapie-infected GPI −/− PrP tg mice failed to develop progressive fatal neurodegenerative disease reminiscent of scrapie infection. Instead, they lived normal life spans of 600 to 700 days but displayed abnormalities in CNS electrophysiology and cognitive learning (Trifilo et al, 2008). In contrast, control mice with a membrane-anchored PrPc developed the expected progressively fatal neurodegenerative disease by 150 to 180 days post-scrapie challenge.…”

Section: Introductionmentioning

confidence: 99%

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Extraneural manifestations of prion infection in GPI-anchorless transgenic mice

et al. 2011

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Earlier studies indicated that transgenic (tg) mice engineered to express prion protein (PrP) lacking the glycophosphatidylinositol (GPI−/−) membrane anchor formed abnormal proteinase-resistant prion (PrPsc) amyloid deposits in their brains and hearts when infected with the RML strain of murine scrapie. In contrast, RML scrapie infection of normal mice with a GPI-anchored PrP did not deposit amyloid with PrPsc in the brain or the heart. Here we report that scrapie-infected GPI−/− PrP tg mice also deposit PrP and transmissible infectious material in the gut, kidneys, and islets of Langerhans. Similar to previously reported amyloid deposits in the brain and heart, amyloid deposits were found in the gut; however, no amyloid deposited in the islets. By high-resolution electron microscopy, we show PrP is located primarily in α cells and also β cells. Islets contain abundant insulin and there is no abnormality in glucose metabolism in infected GPI−/− PrP tg mice.

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Section: Resultssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Extraneural manifestations of prion infection in GPI-anchorless transgenic mice

et al. 2011

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“…This observation suggests that the genetic interaction between PrP C and its neurotoxic variants may physically necessitate membrane anchoring of all relevant partners. In contrast, soluble-dimeric prion protein (PrP-Fc 2 ) was found to translocate to the DRM compartment and to associate with PrP Sc upon prion infection of mice coexpressing PrP C and PrP-Fc 2 [51]. In this context, it may be of interest to study the localization of PrP ΔCDs in prion infected mice.…”

Section: Discussionmentioning

confidence: 99%

Functionally Relevant Domains of the Prion Protein Identified In Vivo

et al. 2009

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The prion consists essentially of PrPSc, a misfolded and aggregated conformer of the cellular protein PrPC. Whereas PrPC deficient mice are clinically healthy, expression of PrPC variants lacking its central domain (PrPΔCD), or of the PrP-related protein Dpl, induces lethal neurodegenerative syndromes which are repressed by full-length PrP. Here we tested the structural basis of these syndromes by grafting the amino terminus of PrPC (residues 1–134), or its central domain (residues 90–134), onto Dpl. Further, we constructed a soluble variant of the neurotoxic PrPΔCD mutant that lacks its glycosyl phosphatidyl inositol (GPI) membrane anchor. Each of these modifications abrogated the pathogenicity of Dpl and PrPΔCD in transgenic mice. The PrP-Dpl chimeric molecules, but not anchorless PrPΔCD, ameliorated the disease of mice expressing truncated PrP variants. We conclude that the amino proximal domain of PrP exerts a neurotrophic effect even when grafted onto a distantly related protein, and that GPI-linked membrane anchoring is necessary for both beneficial and deleterious effects of PrP and its variants.

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“…Preparation of brain homogenate. Three-to 4-week-old mice were inoculated intracerebrally with scrapie agent-infected brain homogenate containing the 22L scrapie strain as described previously (44,60). Wild-type mice were euthanized at the time of clinical signs, around 150 to 160 days postinoculation (dpi).…”

Section: Mouse Linesmentioning

confidence: 99%

Analysis of Protein Levels of 24 Cytokines in Scrapie Agent-Infected Brain and Glial Cell Cultures from Mice Differing in Prion Protein Expression Levels

Tribouillard-Tanvier

Striebel

Peterson

et al. 2009

J Virol

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Activation of microglia and astroglia is seen in many neurodegenerative diseases including prion diseases. Activated glial cells produce cytokines as a protective response against certain pathogens and as part of the host inflammatory response to brain damage. In addition, cytokines might also exacerbate tissue damage initiated by other processes. In the present work using multiplex assays to analyze protein levels of 24 cytokines in scrapie agent-infected C57BL/10 mouse brains, we observed elevation of CCL2, CCL5, CXCL1, CXCL10, granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma interferon (IFN-␥), interleukin 1␣ (IL-1␣), IL-1␤, IL-6, and IL-12p40. Scrapie agent-infected wild-type mice and transgenic mice expressing anchorless prion protein (PrP) had similar cytokine responses in spite of extensive differences in neuropathology. Therefore, these responses may be primarily a reaction to brain damage induced by prion infection rather than specific inducers of a particular type of pathology. To study the roles of astroglia and microglia in these cytokine responses, primary glial cultures were exposed to scrapie agent-infected brain homogenates. Microglia produced only IL-12p40 and CXCL10, whereas astroglia produced these cytokines plus CCL2, CCL3, CCL5, CXCL1, G-CSF, IL-1␤, IL-6, IL-12p70, and IL-13. Glial cytokine responses from wild-type mice and transgenic mice expressing anchorless PrP differed only slightly, but glia from PrP-null mice produced only IL-12p40, indicating that PrP expression was required for scrapie agent induction of other cytokines detected. The difference in cytokine response between microglia and astroglia correlated with 20-fold-higher levels of PrP expression in astroglia versus microglia, suggesting that high-level PrP expression on astroglia might be important for induction of certain cytokines.

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Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic Pathway

Cited by 14 publications

References 36 publications

Extraneural manifestations of prion infection in GPI-anchorless transgenic mice

Extraneural manifestations of prion infection in GPI-anchorless transgenic mice

Functionally Relevant Domains of the Prion Protein Identified In Vivo

Analysis of Protein Levels of 24 Cytokines in Scrapie Agent-Infected Brain and Glial Cell Cultures from Mice Differing in Prion Protein Expression Levels

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