Promising multifunctional anti-Alzheimer's dimer bis(7)-Cognitin acting as an activator of protein kinase C regulates activities of alpha-secretase and BACE-1 concurrently.
We have recently demonstrated that bis(7)-Cognitin, a promising multifunctional anti-Alzheimer's dimer, can remarkably reduce the generation of amyloid beta peptide (Abeta) by inhibiting beta-secretase (BACE-1) and activating alpha-secretase activity. In this study, the mechanism(s) underlying bis(7)-Cognitin's regulation of the activity of these two proteases was further investigated. In N2a cells stably expressing human amyloid precursor protein with the Swedish mutation (APPswe), the reduction in Abeta production induced by 1microM bis(7)-Cognitin was not altered by the co-pretreatment of muscarinic and nicotinic cholinergic receptor antagonists, indicating that the regulation of APP processing by this dimer is independent of cholinergic transmission. Furthermore, bis(7)-Cognitin (0.1-3microM) significantly increased protein kinase C (PKC) activity in cells and in vitro in a concentration-dependent manner. Administration of a PKC activator, phorbol 12-myristate 13-acetate (PMA), concentration-dependently increased the alpha-secretase cleavage products, and reduced the BACE-1 cleavage products. In addition, the inhibition of PKC prevented PMA- or bis(7)-Cognitin-induced alterations in alpha-secretase and BACE-1 activities, eliminating reductions in Abeta production seen with PMA or the dimer. These results strongly suggest that bis(7)-Cognitin may reduce the biosynthesis of Abeta by inhibiting BACE-1 and activating alpha-secretase concurrently through the direct activation of PKC. Combined with previous findings of direct inhibition of AChE and BACE-1 by this dimer, this work indicates that strategy may have potential to provide new insights into designing novel drugs that target multiple steps of aberrant APP processing to treat Alzheimer's disease.
Fu
Hongjun
H
Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hong Kong.
Dou
Juan
J
Li
Wenming
W
Cui
Wei
W
Mak
Shinghung
S
Hu
Qiansheng
Q
Luo
Jialie
J
Lam
Colin S C
CS
Pang
Yuanping
Y
Youdim
Moussa B H
MB
Han
Yifan
Y
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018727:Muscarinic Antagonists / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010703:Phorbol Esters / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D020536:Enzyme Activators; D018727:Muscarinic Antagonists; D050505:Mutant Proteins; D010446:Peptide Fragments; D010703:Phorbol Esters; D020033:Protein Isoforms; D011976:Receptors, Muscarinic; D013619:Tacrine; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases