Prion diseases are disorders of protein conformation in which PrPC, the normal 
cellular conformer, is converted to an abnormal, protease-resistant conformer 
rPrPSc. Approximately 80% of rPrPSc accumulates in neuronal plasma membranes 
where it changes their physical properties and profoundly affects membrane 
functions. In this review we explain how rPrPSc is transported along axons to 
presynaptic boutons and how we envision the conversion of PrPC to rPrPSc in the 
postsynaptic membrane. This information is a prerequisite to the second half of 
this review in which we present evidence that rPrPSc accumulation in synaptic 
regions links Notch-1 signaling with the dendritic degeneration. The hypothesis 
that the Notch-1 intracellular domain, NICD, is involved in prion disease was 
tested by treating prion-infected mice with the gamma-secretase inhibitor (GSI) 
LY411575, with quinacrine (Qa), and with the combination of GSI + Qa. 
Surprisingly, treatment with GSI alone markedly decreased NICD but did not 
prevent dendritic degeneration. Qa alone produced near normal dendritic trees. 
The combined GSI + Qa treatment resulted in a richer dendritic tree than in 
controls. We speculate that treatment with GSI alone inhibited both stimulators 
and inhibitors of dendritic growth. With the combined GSI + Qa treatment, Qa 
modulated the effect of GSI perhaps by destabilizing membrane rafts. GSI + Qa 
decreased PrPSc in the neocortex and the hippocampus by 95%, but only by 50% in 
the thalamus where disease was begun by intrathalamic inoculation of prions. The 
results of this study indicate that GSI + Qa work synergistically to prevent 
dendrite degeneration and to block formation of PrPSc.