Activation of α-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 β-amyloid precursor protein (βAPP) by β- and γ-secretases. A third non-amyloidogenic α-secretase activity performed by the disintegrins ADAM10 and ADAM17 occurs in the middle of the amyloid-β peptide Aβ and liberates the large sAPPα neuroprotective fragment. Since the activation of α-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 α-secretase activators. We established that the aminoacid conjugates curcumin-isoleucine, curcumin-phenylalanine and curcumin-valine promote the constitutive α-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 α-secretase activators and established that some of these molecules are able to discriminate between the constitutive and regulated α-secretase pathways.
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand.
Ramesh B
RB
Narasingappa
Ramesh B
RB
Narasingapa
Manjunatha R
MR
Javagal
Manjunatha R
MR
Jargaval
Srinivas
S
Pullabhatla
Htut Htut
HH
Htoo
Jagannatha K S
JK
Rao
Jean-François
JF
Hernandez
Piyarat
P
Govitrapong
Bruno
B
Vincent
D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D008565:Membrane Proteins; C576679:curcumin-isoleucine; C576680:curcumin-phenylalanine; C576681:curcumin-valine; D007532:Isoleucine; D010649:Phenylalanine; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D014633:Valine; D003474:Curcumin