TY - JOUR
T1 - A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains
AU - Spilman, Patricia
AU - Lessard, Pierre
AU - Sattavat, Mamta
AU - Bush, Clarissa
AU - Tousseyn, Thomas
AU - Huang, Eric J.
AU - Giles, Kurt
AU - Golde, Todd
AU - Das, Pritam
AU - Fauq, Abdul
AU - Prusiner, Stanley B.
AU - DeArmond, Stephen J.
PY - 2008/7/29
Y1 - 2008/7/29
N2 - 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.
AB - 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.
KW - Creutzfeldt-Jakob disease
KW - Neuropathology
KW - Prion disease
KW - Scrapie
KW - Therapy
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U2 - 10.1073/pnas.0803671105
DO - 10.1073/pnas.0803671105
M3 - Article
C2 - 18647832
AN - SCOPUS:48749106225
SN - 0027-8424
VL - 105
SP - 10595
EP - 10600
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -