Effects of Heparin and Enoxaparin on APP Processing and Ab Production in Primary Cortical Neurons from Tg2576 Mice

Background: Alzheimer’s disease (AD) is caused by accumulation of Ab, which is produced through sequential cleavage of b-amyloid precursor protein (APP) by the b-site APP cleaving enzyme (BACE1) and c-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Ab plaque deposition and improve cognitive function in AD transgenic mice. Methodology/Principal Findings: We examined whether heparin and enoxaparin influence APP processing and inhibit Ab production in primary cortical cell cultures. Heparin and enoxaparin were incubated with primary cortical cells derived from Tg2576 mice, and the level of APP and proteolytic products of APP (sAPPa, C99, C83 and Ab) was measured by western blotting. Treatment of the cells with heparin or enoxaparin had no significant effect on the level of total APP. However, both GAGs decreased the level of C99 and C83, and inhibited sAPPa and Ab secretion. Heparin also decreased the level of bsecretase (BACE1) and a-secretase (ADAM10). In contrast, heparin had no effect on the level of ADAM17. Conclusions/Significance: The data indicate that heparin and enoxaparin decrease APP processing via both aand bsecretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study. Citation: Cui H, Hung AC, Klaver DW, Suzuki T, Freeman C, et al. (2011) Effects of Heparin and Enoxaparin on APP Processing and Ab Production in Primary Cortical Neurons from Tg2576 Mice. PLoS ONE 6(7): e23007. doi:10.1371/journal.pone.0023007 Editor: Sergio T. Ferreira, Federal University of Rio de Janeiro, Brazil Received December 2, 2010; Accepted July 11, 2011; Published July 29, 2011 Copyright: ! 2011 Cui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by a project grant (490031) from the National Health and Medical Research Council of Australia (http://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]