Niemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative 
disorder characterized by intracellular accumulation of cholesterol and 
glycosphingolipids in many tissues including the brain. The disease is caused by 
mutations of either NPC1 or NPC2 gene and is accompanied by a severe loss of 
neurons in the cerebellum, but not in the hippocampus. NPC pathology exhibits 
some similarities with Alzheimer's disease, including increased levels of 
amyloid beta (Abeta)-related peptides in vulnerable brain regions, but very 
little is known about the expression of amyloid precursor protein (APP) or APP 
secretases in NPC disease. In this article, we evaluated age-related alterations 
in the level/distribution of APP and its processing enzymes, beta- and 
gamma-secretases, in the hippocampus and cerebellum of Npc1(-/-) mice, a 
well-established model of NPC pathology. Our results show that levels and 
expression of APP and beta-secretase are elevated in the cerebellum prior to 
changes in the hippocampus, whereas gamma-secretase components are enhanced in 
both brain regions at the same time in Npc1(-/-) mice. Interestingly, a subset 
of reactive astrocytes in Npc1(-/-) mouse brains expresses high levels of APP as 
well as beta- and gamma-secretase components. Additionally, the activity of 
beta-secretase is enhanced in both the hippocampus and cerebellum of Npc1(-/-) 
mice at all ages, while the level of C-terminal APP fragments is increased in 
the cerebellum of 10-week-old Npc1(-/-) mice. These results, taken together, 
suggest that increased level and processing of APP may be associated with the 
development of pathology and/or degenerative events observed in Npc1(-/-) mouse 
brains.