Regulation of Secretion of Alzheimer Amyloid Precursor Protein by the Mitogen-Activated Protein Kinase Cascade |
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| Authors: | Juliette Desdouits-Magnen Frédéric Desdouits Shizu Takeda Li-Jyun Syu Alan R Saltiel Joseph D Buxbaum rew J Czernik Angus C Nairn Paul Greengard |
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| Institution: | Laboratory of Molecular and Cellular Neuroscience and Zachary and Elizabeth M. Fisher Center for Research on Alzheimer's Disease, Rockefeller University, New York, New York;and; Department of Signal Transduction, Parke-Davis Pharmaceutical Research, Warner Lambert Company, Ann Arbor, Michigan, U.S.A. |
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| Abstract: | Abstract: Activation of protein kinase C (PKC) regulates the processing of Alzheimer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid β-peptide (Aβ). However, little is known about the intermediate steps between PKC activation and modulation of APP metabolism. Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant of MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechanism involving activation of the MAP kinase cascade. In PC12-M1 cells, activation of MAP kinase by nerve growth factor was associated with stimulation of sAPP release. Conversely, M1 muscarinic receptor stimulation, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathway. Aβ secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for Aβ and sAPP formation. |
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| Keywords: | Amyloid β-peptide Alzheimer disease Protein kinase C Mitogen-activated protein kinase |
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