Substrate-Specific Activation of alpha-Secretase by 7-Deoxy-Trans-Dihydronarciclasine Increases Non-Amyloidogenic Processing of beta-Amyloid Protein Precursor

Accumulation of beta-amyloid (A beta) in the brain has been implicated in the pathology of Alzheimer's disease (AD). A beta is produced from the A beta precursor protein (APP) through the amyloidogenic pathway by beta-, and gamma-secretase. Alternatively, APP can be cleaved by alpha-, and gamma-secretase, precluding the production of A beta. Thus, stimulating alpha-secretase mediated APP processing is considered a therapeutic option not only for decreasing A beta production but for increasing neuroprotective sAPP alpha. We have previously reported that 7-deoxy-trans-dihydronarciclasine (E144), the active component of Lycoris chejuensis, decreases A beta production by attenuating APP level, and retarding APP maturation. It can also improve cognitive function in the AD model mouse. In this study, we further analyzed the activating effect of E144 on alpha-secretase. Treatment of E144 increased sAPP alpha, but decreased beta-secretase products from HeLa cells stably transfected with APP. E144 directly activated ADAM10 and ADAM17 in a substrate-specific manner both in cell-based and in cell-free assays. The Lineweaver-Burk plot analysis revealed that E144 enhanced the affinities of A Disintegrin and Metalloproteinases (ADAMs) towards the substrate. Consistent with this result, immunoprecipitation analysis showed that interactions of APP with ADAM10 and ADAM17 were increased by E144. Our results indicate that E144 might be a novel agent for AD treatment as a substrate-specific activator of alpha-secretase.