Most familial early-onset Alzheimer's disease (FAD) is caused by mutations in the
presenilin-1 (PS1) gene. Abeta is derived from amyloid precursor protein (APP) and
an increased concentration of Abeta 42 is widely believed to be a pathological hallmark
of abnormal PS function. Therefore, the interaction between PS1 and APP is a central
theme in attempts to clarify the molecular mechanism of AD. To examine the effect
of PS1 mutations on APP metabolism, we made PC12D cell lines that express human PS1
or mutant PS1 (A260V). In PC12D cells expressing the PS1A260V mutant, we found that
Rab8, a GTPase involved in transport from the trans-Golgi network (TGN) to the plasma
membrane (PM), was significantly reduced in PC12D cells expressing the A260V mutant
and that APP C-terminal fragment (CTF), the direct precursor of Abeta, accumulated
in the heavy membrane fraction including membrane vesicles involved in TGN-to-PM transport.
Furthermore, the total intracellular Abeta production was reduced in these cells.
Combined together, we have observed that PS1 mutation disturbs membrane vesicle transport,
resulting in prolonged residence of APP CTF during TGN-to-PM transport pathway. Therefore,
it is highly likely that reduction of Abeta is closely related to the retention of
APP CTF during TGN-to-PM transport.