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Size and sulfation are critical for the effect of heparin on APP processing and A beta production

Citation

Cui, H and Hung, AC and Freeman, C and Narkowicz, C and Jacobson, GA and Small, DH, Size and sulfation are critical for the effect of heparin on APP processing and A beta production, Journal of Neurochemistry, 123, (3) pp. 447-457. ISSN 0022-3042 (2012) [Refereed Article]

Copyright Statement

Copyright 2012 the authors.

DOI: doi:10.1111/j.1471-4159.2012.07929.x

Abstract

Abstract Alzheimers disease (AD) is associated with abnormal accumulation of A, which is produced from the -amyloid precursor protein (APP) by the -site APP cleaving enzyme (BACE1) and -secretase. Our previous studies showed that heparin can decrease APP processing by decreasing the levels of BACE1 and ADAM10. In the present study, we examined the effects of glycosaminoglycans (GAGs) on APP processing and A production with the aim of understanding the specificity of the effects. Various GAG analogues were incubated with primary cortical cells derived from APP(SW)Tg2576 mice and the level of APP, proteolytic products of APP and APP cleavage enzymes were measured. The effect of GAGs on APP processing was both size- and sulfation-dependent. 6-O-Sulfation was important for the effect on APP processing as heparin lacking 6-O sulfate were less potent than native heparin. However, deletion of carboxyl groups on MH had no significant effect on APP processing. Our studies suggest that there is structural specificity to the effect of GAGs on APP processing and that certain GAGs have a greater effect on A production than others. This suggests that it might be possible to alter the structure of GAGs to achieve more specific inhibitors of APP processing that can cross the blood brain barrier.

Item Details

Item Type:Refereed Article
Keywords:Alzheimers disease, amyloid, glycosaminoglycan, sulfation
Research Division:Medical and Health Sciences
Research Group:Pharmacology and Pharmaceutical Sciences
Research Field:Basic Pharmacology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Cui, H (Mr Hao Cui)
Author:Hung, AC (Dr Amos Hung)
Author:Narkowicz, C (Dr Christian Narkowicz)
Author:Jacobson, GA (Dr Glenn Jacobson)
Author:Small, DH (Professor David Small)
ID Code:79909
Year Published:2012
Web of Science® Times Cited:7
Deposited By:Pharmacy
Deposited On:2012-10-11
Last Modified:2015-02-12
Downloads:0

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