Inducible neuronal PrP knockout mice reveal potential therapeutic window for TSE intervention

B.M. Bradford, A.S. Marshall, D.A. Brown, Dorothy Kisielewski, N.L. Tuzi, Pedro Piccardo, A. Clarke, V.H. Perry, J.C. Manson

Research output: Contribution to journalMeeting abstract

Abstract

It is known that expression of the host form of PrP protein (PrPC) is required for susceptibility to and the establishment of transmissible spongiform encephalopathies (TSEs). We have produced a Cre/LoxP conditional PrP knockout mouse model in which administration of tamoxifen results in the removal of PrPC expression from neurones only. Using this model we have previously demonstrated that removal of PrPC expression from neurones prior to infection with the ME7 mouse-adapted Scrapie strain dramatically altered pathology, preventing spongiosis and neuronal loss in specific neuronal populations, and greatly extended disease incubation period. As a further application of this model, neuronal PrP knockout was induced in groups of mice at various time-points post intra-cerebral ME7 infection to assess the impact upon disease pathogenesis. Results indicate that early in the incubation period there are time-points where neuronal PrPC expression is essential for ‘normal’ disease progression, but at later stages removal of neuronal PrPC no longer influenced disease incubation period. This critical time-point occurs after known pathologies such as synaptic loss have become established within the central nervous system.

These results assist in informing us of the basic mechanisms in TSE neurodegeneration and also of a ‘time-window’ when potential therapeutic intervention involving the reduction of PrPC expression may be possible in TSE diseases. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.
Original languageEnglish
Pages (from-to)173
Number of pages1
JournalPrion
Volume4
Issue number3
Publication statusPublished - 2010
EventPrion 2010 - Salzburg, Austria
Duration: 8 Sep 201011 Sep 2010

Keywords

  • neurodegeneration tamoxifen inducible Cre/LoxP PrP knockout

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