New Protein Kinase C Activator Regulates Amyloid Precursor Protein Processing In Vitro By Increasing Alpha-Secretase Activity
The European journal of neuroscience(2007)
Abstract
The beta amyloid (A beta) 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 sAPP alpha without affecting full-length expression of APP. The increase in sAPP alpha 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 sAPP alpha 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, A beta 40 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.
MoreTranslated text
Key words
Alzheimer's disease,amyloid precursor protein,protein kinase C,sAPP alpha,beta-amyloid
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined