Activation of alpha-secretase by curcumin-aminoacid conjugates.

The extracellular senile plaques observed in Alzheimer’s disease (AD) patients are mainly composed of
amyloid peptides produced from the b-amyloid precursor protein (bAPP) by b- and c-secretases. A third
non-amyloidogenic a-secretase activity performed by the disintegrins ADAM10 and ADAM17 occurs in
the middle of the amyloid-b peptide Ab and liberates the large sAPPa neuroprotective fragment. Since
the activation of a-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 a-secretase activators. We established that the aminoacid
conjugates curcumin–isoleucine, curcumin–phenylalanine and curcumin–valine promote the constitutive
a-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 a-secretase activators and established that some of these
molecules are able to discriminate between the constitutive and regulated a-secretase pathways