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

Alzheimer's disease is associated with abnormal accumulation of Aβ, which is produced from the β‐amyloid precursor protein (APP) by the β‐site APP‐cleaving enzyme (BACE1) and γ‐secretase. Our previous studies showed that heparin can decrease APP processing by decreasing the levels of BACE1 and ADAM10. In this study, we examined the effects of glycosaminoglycans (GAGs) on APP processing and Aβ production with the aim of understanding the specificity of the effects. Various GAG analogs 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 heparin 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 Aβ 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.