Effects of heparin and enoxaparin on APP processing and A beta production in primary cortical neurons from Tg2576 mice

Alzheimer s disease (AD) is caused by accumulation of Abeta, which is produced through sequential cleavage of beta-amyloid precursor protein (APP) by the beta-site APP cleaving enzyme (BACE1) and gamma-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Abeta plaque deposition and improve cognitive function in AD transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: We examined whether heparin and enoxaparin influence APP processing and inhibit Abeta 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 (sAPPalpha, C99, C83 and Abeta) 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 sAPPalpha and Abeta secretion. Heparin also decreased the level of beta-secretase (BACE1) and alpha-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 alpha- and beta-secretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study.