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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-beta (Abeta ) from the amyloid precursor protein (APP) requires proteolytic cleavage by two proteases, beta - and gamma -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 gamma -secretase-associated presenilins (PS). Exposure of neuronal cells to cholesterol transport-inhibiting agents resulted in a marked decrease in beta -cleavage of full-length APP. In contrast, gamma -secretase activity on APP C-terminal fragments was enhanced, increasing the production of both Abeta 40 and Abeta 42. 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 Abeta 42 also localized to PS1-containing vesicular compartments, organelles involved in cholesterol transport might represent an important site for gamma -secretase activity. Our results suggest that the subcellular distribution of cholesterol may be an important factor in how cholesterol alters Abeta production and the risk of Alzheimer's disease.

Key words: presenilin; cholesterol; NPC1; APP processing; Rab7; ACAT; amyloid-beta

Copyright © 2002 Society for Neuroscience  0270-6474/02/2251679-11$05.00/0


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