New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing alpha-secretase activity.
The beta amyloid (Abeta) cascade has been at the forefront of the hypothesis used to describe the pathogenesis of Alzheimer's disease (AD). It is generally accepted that drugs that can regulate the processing of the amyloid precursor protein (APP) toward the non-amyloidogenic pathway may have a therapeutic potential. Previous studies have shown that protein kinase C (PKC) hypofunction has an important role in AD pathophysiology. Therefore, the effects of a new PKC activator, alpha-APP modulator [(2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB)], on APP processing were investigated. Using PC12 cells and SH-SY5Y(APP695) cells, it was found that TPPB promoted the secretion of sAPPalpha without affecting full-length expression of APP. The increase in sAPPalpha by TPPB was blocked by inhibitors of PKC, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and tyrosine kinase, suggesting the involvement of these signal transduction pathways. TPPB increased alpha-secretase activity [a disintegrin and metalloproteinase (ADAM)10 and 17], as shown by direct fluorescence activity detection and Western blot analysis. TPPB-induced sAPPalpha release was blocked by the metalloproteinase inhibitor TAPI-2, furin inhibitor CMK and by the protein-trafficking inhibitor brefeldin. The results also showed that TPPB decreased beta-secretase activity, Abeta40 release and beta site APP-cleaving enzyme 1 (BACE1) expression, but did not significantly affect neprilysin (NEP) and insulin-degrading enzyme (IDE) expression. Our data indicate that TPPB could direct APP processing towards the non-amyloidogenic pathway by increasing alpha-secretase activity, and suggest its therapeutic potential in AD.
Yang
Hong-Qi
HQ
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China.
Pan
Jing
J
Ba
Mao-Wen
MW
Sun
Zhi-Kun
ZK
Ma
Guo-Zhao
GZ
Lu
Guo-Qiang
GQ
Xiao
Qin
Q
Chen
Sheng-Di
SD
D000199:Actins / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D020536:Enzyme Activators / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D016716:PC12 Cells; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D014178:Translocation, Genetic
C471167:8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam V; D000199:Actins; D016564:Amyloid beta-Protein Precursor; D001570:Benzodiazepinones; D020536:Enzyme Activators; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D053829:Amyloid Precursor Protein Secretases