Cholesterol transport is a key regulator of
amyloid precursor
protein (APP) processing and
beta-amyloid (Abeta production, implicated in
Alzheimer's disease. Perturbation of
cholesterol transport can be pharmacologically induced by the class II amphiphile 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one,
U18666a; however, the mechanisms by which
U18666a controls APP metabolism and trafficking have not been elucidated. We proposed to determine how
U18666a regulates APP holoprotein metabolism and trafficking in N2a mouse
neuroblastoma cells stably expressing the
human APP protein. Secretion of Abeta1-40 was reduced in
U18666a-treated cells.
U18666a elevated the steady state level of the APP holoprotein but not APP
mRNA levels.
U18666a increased sAPPalpha secretion and intracellular alpha-CTF/C83 levels but intracellular betaCTF/C99 levels were reduced. The increase in APP
protein level was due to decreased catabolism rather than increased APP synthesis. Interestingly,
U18666a regulated APP trafficking and increased the level of the holoprotein at the cell surface for
alpha-secretase processing and reduced internalization for
beta-secretase processing. These data demonstrate that
U18666a effects on
cholesterol transport function to regulate
amyloid precursor
protein metabolism and trafficking.