Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing...

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Main Authors:	Ehehalt, Robert, Keller, Patrick, Haass, Christian, Thiele, Christoph, Simons, Kai
Format:	Online
Language:	English
Published:	The Rockefeller University Press 2003
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172747/

id	pubmed-2172747
recordtype	oai_dc
spelling	pubmed-21727472008-05-01 Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts Ehehalt, Robert Keller, Patrick Haass, Christian Thiele, Christoph Simons, Kai Article Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts. The Rockefeller University Press 2003-01-06 /pmc/articles/PMC2172747/ /pubmed/12515826 http://dx.doi.org/10.1083/jcb.200207113 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ehehalt, Robert Keller, Patrick Haass, Christian Thiele, Christoph Simons, Kai
spellingShingle	Ehehalt, Robert Keller, Patrick Haass, Christian Thiele, Christoph Simons, Kai Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
author_facet	Ehehalt, Robert Keller, Patrick Haass, Christian Thiele, Christoph Simons, Kai
author_sort	Ehehalt, Robert
title	Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
title_short	Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
title_full	Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
title_fullStr	Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
title_full_unstemmed	Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
title_sort	amyloidogenic processing of the alzheimer β-amyloid precursor protein depends on lipid rafts
description	Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.
publisher	The Rockefeller University Press
publishDate	2003
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172747/
_version_	1611425037042057216

Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

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