Mitogen activated protein kinase and protein kinase C activation mediate promotion of sAPPalpha secretion by deprenyl.
The beta amyloid cascade plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Therefore, drugs that regulate amyloid precursor protein (APP) processing toward the nonamyloidgenic pathway may have therapeutic potential. Many anti-dementia drugs can regulate APP processing in addition to their pharmacological properties. Deprenyl is a neuroprotective agent used to treat some neurodegenerative diseases, including AD. In the present study, the effects of deprenyl on APP processing were investigated. Using SK-N-SH and PC12 cells, it was demonstrated that deprenyl stimulated the release of the nonamyloidogenic alpha-secretase form of soluble APP (sAPPalpha) in a dose-dependent manner without affecting cellular APP expression. The increase of sAPPalpha secretion by deprenyl was blocked by the mitogen activated protein (MAP) kinase inhibitor U0126 and PD98059, and by the protein kinase C (PKC) inhibitor GF109203X and staurosporine, suggesting the involvement of these signal transduction pathways. Deprenyl induced phosphorylation of p42/44 MAP kinase, which was abolished by specific inhibitors of MAP kinase and PKC. Deprenyl also phosphorylated PKC and its major substrate, and myristoylated alanine-rich C kinase (MARCKS) at specific amino acid residues. The data also indicated that 10microM deprenyl successfully induced two PKC isoforms involved in the pathogenesis of AD, PKCalpha and PKCepsilon, to translocate from the cytosolic to the membrane fraction. This phenomenon was substantiated by immunocytochemistry staining. These data suggest a novel pharmacological mechanism in which deprenyl regulates the processing of APP via activation of the MAP kinase and PKC pathways, and that this mechanism may underlie the clinical efficacy of the drug in some AD patients.
Yang
Hong-Qi
HQ
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
Ba
Mao-Wen
MW
Ren
Ru-Jing
RJ
Zhang
Yu-Hong
YH
Ma
Jian-Fang
JF
Pan
Jing
J
Lu
Guo-Qiang
GQ
Chen
Sheng-Di
SD
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D012642:Selegiline / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; D008301:Maleimides; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D012642:Selegiline; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C070515:bisindolylmaleimide I