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Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase

Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavag...

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Autores principales: Scholefield, Zoe, Yates, Edwin A., Wayne, Gareth, Amour, Augustin, McDowell, William, Turnbull, Jeremy E.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173449/
https://www.ncbi.nlm.nih.gov/pubmed/14530380
http://dx.doi.org/10.1083/jcb.200303059
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author Scholefield, Zoe
Yates, Edwin A.
Wayne, Gareth
Amour, Augustin
McDowell, William
Turnbull, Jeremy E.
author_facet Scholefield, Zoe
Yates, Edwin A.
Wayne, Gareth
Amour, Augustin
McDowell, William
Turnbull, Jeremy E.
author_sort Scholefield, Zoe
collection PubMed
description Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by α-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing.
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spelling pubmed-21734492008-05-01 Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase Scholefield, Zoe Yates, Edwin A. Wayne, Gareth Amour, Augustin McDowell, William Turnbull, Jeremy E. J Cell Biol Article Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by α-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing. The Rockefeller University Press 2003-10-13 /pmc/articles/PMC2173449/ /pubmed/14530380 http://dx.doi.org/10.1083/jcb.200303059 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/).
spellingShingle Article
Scholefield, Zoe
Yates, Edwin A.
Wayne, Gareth
Amour, Augustin
McDowell, William
Turnbull, Jeremy E.
Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase
title Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase
title_full Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase
title_fullStr Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase
title_full_unstemmed Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase
title_short Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase
title_sort heparan sulfate regulates amyloid precursor protein processing by bace1, the alzheimer's β-secretase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173449/
https://www.ncbi.nlm.nih.gov/pubmed/14530380
http://dx.doi.org/10.1083/jcb.200303059
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