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The Journal of Neuroscience, March 1, 2002, 22(5):1679-1689
Inhibition of Intracellular Cholesterol Transport Alters
Presenilin Localization and Amyloid Precursor Protein Processing in
Neuronal Cells
Heiko
Runz1, 2,
Jens
Rietdorf2,
Inge
Tomic1,
Marina
de
Bernard3,
Konrad
Beyreuther1,
Rainer
Pepperkok2, and
Tobias
Hartmann1
1 Center for Molecular Biology, University of
Heidelberg, 69120 Heidelberg, Germany, 2 European Molecular
Biology Laboratory, 69117 Heidelberg, Germany, and
3 Department of Biomedical Science, University of Padua,
35121 Padua, Italy
Generation of amyloid- (A) from the amyloid precursor protein
(APP) requires proteolytic cleavage by two proteases, - and  -secretase. Several lines of evidence suggest a role for cholesterol on secretase activities, although the responsible cellular mechanisms remain unclear. Here we show that alterations in cholesterol transport from late endocytic organelles to the endoplasmic reticulum have important consequences for both APP processing and the localization of
-secretase-associated presenilins (PS). Exposure of neuronal cells
to cholesterol transport-inhibiting agents resulted in a marked
decrease in -cleavage of full-length APP. In contrast, -secretase
activity on APP C-terminal fragments was enhanced, increasing the
production of both A40 and A42. Remarkably, retention of
cholesterol in endosomal/lysosomal compartments induced PS1 and PS2 to
accumulate in Rab7-positive vesicular organelles implicated in
cholesterol sorting. Accumulation of PS in vesicular compartments was
prominent in both Chinese hamster ovary cells deficient in Niemann-Pick C1 protein as well as in neuronal cells exposed to the
cholesterol transport-inhibiting agent U18666A. Because A42 also
localized to PS1-containing vesicular compartments, organelles involved
in cholesterol transport might represent an important site for
-secretase activity. Our results suggest that the subcellular distribution of cholesterol may be an important factor in how cholesterol alters A production and the risk of Alzheimer's disease.
Key words:
presenilin; cholesterol; NPC1; APP processing; Rab7; ACAT; amyloid-
Copyright © 2002 Society for Neuroscience 0270-6474/02/2251679-11$05.00/0
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