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Published online 6 October 2003. doi:10.1083/jcb.200303059
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© The Rockefeller University Press, 0021-9525/2003/10/97 $8.00
The Journal of Cell Biology, Volume 163, Number 1, 97-107

Article

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



Zoe Scholefield1, Edwin A. Yates1, Gareth Wayne2, Augustin Amour2, William McDowell2 and Jeremy E. Turnbull1

1 School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK
2 GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK

Address correspondence to Jeremy Turnbull at his present address School of Biological Sciences, University of Liverpool, Crown St., Liverpool, L69 7ZB, UK. Tel.: 44-151-795-4427. Fax.: 44-870-121-0564. email: j.e.turnbull{at}liv.ac.uk

Cleavage of amyloid precursor protein (APP) by the Alzheimer's ß-secretase (BACE1) is a key step in generating amyloid ß-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with ß-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 {alpha}-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.

Key Words: Alzheimer's disease; amyloid processing; proteoglycan; protease; neurodegeneration

Abbreviations used in this paper: Aß, amyloid ß-peptide; AD, Alzheimer's disease; APP, amyloid precursor protein; BACE, ß-site APP-cleaving enzyme; BLH, bovine lung heparin; C99, membrane-bound COOH-terminal fragment; DS, dermatan sulfate; HEK-BACE1, HEK293T cells stably transfected with myc-tagged BACE1; HS, heparan sulfate; HSPG, HS proteoglycan; PMHS, porcine mucosal HS; sAPPß, soluble NH2-terminal fragment; SHswAPP, SHSY5Y neuroblastoma cells expressing APP with the Swedish mutation; SWDC1, HEK293T cells expressing APP with the Swedish mutation.


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