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PMID: 11880497 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 5 ·2002-03-01 ·Pages 1679-89

Runz H, Rietdorf J, Tomic I, de Bernard M, Beyreuther K, Pepperkok R, Hartmann T

Abstract

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 Abeta40 and Abeta42. 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 Abeta42 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.

MeSH Terms
Amyloid Precursor Protein Secretases Amyloid beta-Protein Precursor/metabolism Animals Aspartic Acid Endopeptidases Biological Transport/drug effects,physiology Cell Compartmentation/physiology Cells, Cultured Cholesterol/metabolism Cricetinae Cytoplasmic Vesicles/metabolism Endopeptidases/metabolism Fibroblasts/cytology,metabolism Humans Intracellular Fluid/metabolism Membrane Proteins/metabolism Mice Neurons/cytology,metabolism Presenilin-1 Presenilin-2 Protein Processing, Post-Translational/physiology Protein Transport/physiology Rats rab GTP-Binding Proteins/metabolism rab7 GTP-Binding Proteins
Chemicals
Amyloid beta-Protein Precursor Membrane Proteins PSEN1 protein, human PSEN2 protein, human Presenilin-1 Presenilin-2 rab7 GTP-Binding Proteins rab7 GTP-binding proteins, human rab7 GTP-binding proteins, mouse rab7 GTP-binding proteins, rat Cholesterol Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse rab GTP-Binding Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Runz Heiko
Center for Molecular Biology, University of Heidelberg, 69120 Heidelberg, Germany. [email protected]
Rietdorf Jens
Tomic Inge
de Bernard Marina
Beyreuther Konrad
Pepperkok Rainer
Hartmann Tobias
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Email
[email protected]
Published
2002-03-01
Pages
1679-89
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6758870
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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