A gamma-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains.
In prion-infected mice, both the Notch-1 intracellular domain transcription factor (NICD) and the disease-causing prion protein (PrP(Sc)) increase in the brain preceding dendritic atrophy and loss. Because the drug LY411575 inhibits the gamma-secretase-catalyzed cleavage of Notch-1 that produces NICD, we asked whether this gamma-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 PrP(Sc) levels in brain, we added quinacrine (Qa) to the treatment regimen. Qa inhibits PrP(Sc) formation in cultured cells. The combination of GSI and Qa reduced PrP(Sc) by approximately 95% in the neocortex and hippocampus but only approximately 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 PrP(Sc) 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.
Spilman
Patricia
P
Departments of Pathology and Neurology and Institute for Neurodegenerative Disease, University of California, San Francisco, CA 94143, USA.
Lessard
Pierre
P
Sattavat
Mamta
M
Bush
Clarissa
C
Tousseyn
Thomas
T
Huang
Eric J
EJ
Giles
Kurt
K
Golde
Todd
T
Das
Pritam
P
Fauq
Abdul
A
Prusiner
Stanley B
SB
Dearmond
Stephen J
SJ
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D003712:Dendrites / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000473:pathology*; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology*; D013997:Time Factors
D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D011328:Prions; D053829:Amyloid Precursor Protein Secretases; D011796:Quinacrine; D000409:Alanine