Protein Kinase C Activation Increases Release of Secreted Amyloid Precursor Protein without Decreasing Aβ Production in Human Primary Neuron Cultures.

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Abstract
Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid β peptide (Aβ) production are believed to play a major role in Alzheimer’s disease (AD). Therefore, reducing Aβ 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 Aβ release (Buxbaum et al., 1993; Gadzuba et al., 1993; Hung et al., 1993). 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 Aβ. 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 Aβ levels.