title: Protein kinase C activation increases release of secreted amyloid precursor protein without decreasing Abeta production in human primary neuron cultures.
abstract: Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid beta peptide (Abeta) production are believed to play a major role in Alzheimer's disease (AD). Therefore, reducing Abeta production in the brain is a possible therapy for AD. Because AD pathology is fairly restricted to the CNS of humans, we have established human cerebral primary neuron cultures to investigate the metabolism of APP. In many cell lines and rodent primary neuron cultures, phorbol ester activation of protein kinase C (PKC) increases the release of the secreted large N-terminal fragment of amyloid precursor protein (sAPP) and decreases Abeta release (; ; ). In contrast, we find that PKC activation in human primary neurons increases the rate of sAPP release and the production of APP C-terminal fragments and 4 kDa Abeta. Our results indicate species- and cell type-specific regulation of APP metabolism. Therefore, our results curtail the use of PKC activators in controlling human brain Abeta levels.
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2T6.
authors.forename: A C
authors.initials: AC
authors.lastname: LeBlanc
authors.forename: M
authors.initials: M
authors.lastname: Koutroumanis
authors.forename: C G
authors.initials: CG
authors.lastname: Goodyer
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation; D005333:Fetus / Q000166:cytology; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D002273:Carcinogens; D010703:Phorbol Esters; D011493:Protein Kinase C