Document Detail

Generation of Alzheimer disease-associated amyloid β42/43 peptide by γ-secretase can be inhibited directly by modulation of membrane thickness.
MedLine Citation:
PMID:  22532566     Owner:  NLM     Status:  MEDLINE    
Pathogenic generation of amyloid β-peptide (Aβ) by sequential cleavage of β-amyloid precursor protein (APP) by β- and γ-secretases is widely believed to causally underlie Alzheimer disease (AD). β-Secretase initially cleaves APP thereby generating a membrane-bound APP C-terminal fragment, from which γ-secretase subsequently liberates 37-43-amino acid long Aβ species. Although the latter cleavages are intramembranous and although lipid alterations have been implicated in AD, little is known of how the γ-secretase-mediated release of the various Aβ species, in particular that of the pathogenic longer variants Aβ(42) and Aβ(43), is affected by the lipid environment. Using a cell-free system, we have directly and systematically investigated the activity of γ-secretase reconstituted in defined model membranes of different thicknesses. We found that bilayer thickness is a critical parameter affecting both total activity as well as cleavage specificity of γ-secretase. Whereas the generation of the pathogenic Aβ(42/43) species was markedly attenuated in thick membranes, that of the major and rather benign Aβ(40) species was enhanced. Moreover, the increased production of Aβ(42/43) by familial AD mutants of presenilin 1, the catalytic subunit of γ-secretase, could be substantially lowered in thick membranes. Our data demonstrate an effective modulation of γ-secretase activity by membrane thickness, which may provide an approach to lower the generation of the pathogenic Aβ(42/43) species.
Edith Winkler; Frits Kamp; Johannes Scheuring; Amelie Ebke; Akio Fukumori; Harald Steiner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-24
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-18     Completed Date:  2012-08-24     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21326-34     Citation Subset:  IM    
Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University Munich, Schillerstrasse 44, 80336 Munich, Germany.
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MeSH Terms
Alzheimer Disease / metabolism*,  pathology
Amyloid Precursor Protein Secretases / genetics,  metabolism*
Amyloid beta-Peptides / genetics,  metabolism*
Cell Membrane / metabolism*,  pathology
HEK293 Cells
Membrane Lipids / genetics,  metabolism*
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Membrane Lipids; EC 3.4.-/Amyloid Precursor Protein Secretases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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