The extracellular senile plaques observed in Alzheimer's disease (AD) patients are mainly composed of amyloid peptides produced from the beta-amyloid precursor protein (beta APP) by beta- and gamma-secretases. A third non-amyloidogenic alpha-secretase activity performed by the disintegrins ADAM10 and ADAM17 occurs in the middle of the amyloid-beta peptide A beta and liberates the large sAPP alpha neuroprotective fragment. Since the activation of alpha-secretase recently emerged as a promising therapeutic approach to treat AD, the identification of natural compounds able to trigger this cleavage is highly required. Here we describe new curcumin-based modified compounds as alpha-secretase activators. We established that the aminoacid conjugates curcumin-isoleucine, curcumin-phenylalanine and curcumin-valine promote the constitutive alpha-secretase activity and increase ADAM10 immunoreactivity. Strickingly, experiments carried out under conditions mimicking the PKC/muscarinic receptor-regulated pathway display different patterns of activation by these compounds. Altogether, our data identified new lead natural compounds for the future development of powerful and stable alpha-secretase activators and established that some of these molecules are able to discriminate between the constitutive and regulated alpha-secretase pathways. (c) 2012 Elsevier Inc. All rights reserved.