A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains

Patricia Spilman, Pierre Lessard, Mamta Sattavat, Clarissa Bush, Thomas Tousseyn, Eric J. Huang, Kurt Giles, Todd Golde, Pritam Das, Abdul Fauq, Stanley B. Prusiner, Stephen J. DeArmond

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Abstract

In prion-infected mice, both the Notch-1 intracellular domain transcription factor (NICD) and the disease-causing prion protein (PrPSc) increase in the brain preceding dendritic atrophy and loss. Because the drug LY411575 inhibits the γ-secretase-catalyzed cleavage of Notch-1 that produces NICD, we asked whether this γ-secretase inhibitor (GSI) might prevent dendritic degeneration in mice with scrapie. At 50 d postinoculation with Rocky Mountain Laboratory (RML) prions, mice were given GSI orally for 43-60 d. Because we did not expect GSI to produce a reduction of PrPSc levels in brain, we added quinacrine (Qa) to the treatment regimen. Qa inhibits PrPSc formation in cultured cells. The combination of GSI and Qa reduced PrP Sc by ≈95% in the neocortex and hippocampus but only ≈50% in the thalamus at the site of prion inoculation. The GSI plus Qa combination prevented dendritic atrophy and loss, but GSI alone did not. Even though GSI reduced NICD levels to a greater extent than GSI plus Qa, it was unable to prevent dendritic degeneration. Whether a balance between NICD and dendrite growth-stimulating factors was achieved with GSI plus Qa but not GSI alone remains to be determined. Although the combination of GSI and Qa diminished PrPSc in the brains of RML-infected mice, GSI toxicity prevented us from being able to assess the effect the GSI plus Qa combination on incubation times. Whether less toxic GSIs can be used in place of LY411575 to prolong survival remains to be determined.

Original languageEnglish (US)
Pages (from-to)10595-10600
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number30
DOIs
StatePublished - Jul 29 2008

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Keywords

  • Creutzfeldt-Jakob disease
  • Neuropathology
  • Prion disease
  • Scrapie
  • Therapy

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Spilman, P., Lessard, P., Sattavat, M., Bush, C., Tousseyn, T., Huang, E. J., Giles, K., Golde, T., Das, P., Fauq, A., Prusiner, S. B., & DeArmond, S. J. (2008). A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains. Proceedings of the National Academy of Sciences of the United States of America, 105(30), 10595-10600. https://doi.org/10.1073/pnas.0803671105