In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic 
atrophy is a prominent feature of prion disease. Because increased Notch-1 
expression and cleavage releasing its intracellular domain (NICD) inhibit both 
dendrite growth and maturation, we measured their levels in brains from mice 
inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was 
elevated in the neocortex, whereas the level of beta-catenin, which stimulates 
dendritic growth, was unchanged. During the incubation period, levels of the 
disease-causing prion protein isoform, PrPSc, and NICD increased concomitantly 
in the neocortex. Additionally, increased levels of Notch-1 mRNA and 
translocation of NICD to the nucleus correlated well with regressive dendritic 
changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was 
elevated compared with uninfected control (N2a) cells. Long neurofilament 
protein-containing processes extended from the surface of N2a cells, whereas 
ScN2a cells had substantially shorter processes. Transfection of ScN2a cells 
with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished 
NICD concentrations, and rescued the long process phenotype. These results 
suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, 
resulting in atrophy of dendrites in the CNS and shrinkage of processes on the 
surface of cultured cells. Whether diminishing Notch-1 activation in vivo can 
prevent or even reverse neurodegeneration in prion disease remains to be 
established.