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The Journal of Neuroscience, April 15, 1998, 18(8):2907-2913

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

Andréa C. LeBlanc^{1, 3}, Maria Koutroumanis³, and Cynthia G. Goodyer²

Departments of ¹ Neurology and Neurosurgery and ² Pediatrics, McGill University, Montreal, Quebec, Canada H3A 2T6, and ³ The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2

Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid  peptide (A) production are believed to play a major role in Alzheimer's disease (AD). Therefore, reducing A 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 A 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 A. 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 A levels.

Key words: amyloid precursor protein metabolism; protein kinase C; amyloid  peptide; secreted amyloid precursor protein; phorbol esters; Alzheimer's disease

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1882907-07$05.00/0

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