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P4–059: Effect of cAMP dependent protein kinase inhibitors on APP processing in HEK293 cells overexpressing human APP
Author(s) -
Su Yuan
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1797
Subject(s) - amyloid precursor protein , western blot , transfection , secretion , protein kinase a , intracellular , hek 293 cells , kinase , amyloid precursor protein secretase , extracellular , microbiology and biotechnology , p3 peptide , amyloid (mycology) , chemistry , biochemistry , biology , alzheimer's disease , medicine , receptor , gene , inorganic chemistry , disease
Background: Alzheimer’s disease (AD) is characterized pathologically by extracellular amyloid peptide (Abeta) deposition in select regions of brain. Abeta peptide, ranging from 38 to 43 residues, is generated by sequential proteolysis of the amyloid precursor protein (APP) by betaand gamma-secretases. It is also the primary component of amyloid plaques in affected brain regions of patients with AD. Objective(s): Although it is known that intracellular APP is subjected to post-translational modification, the molecular mechanism that regulates the APP processing is not completely understood. In the present study, we demonstrated that H89 and PKI, selective inhibitors of cAMP dependent protein kinase (PKA), concentration-dependently inhibited Abeta production and soluble APP secretion in cells stably transfected with human APP. Concurrent with these effects, H89 also attenuated the accumulation of carboxyl-terminal fragments of APP, assessed by Western blot. In addition, PKA inhibitor (H89) abolished the maturation of APP in these cells. Methods: Although it is known that intracellular APP is subjected to post-translational modification, the molecular mechanism that regulates the APP processing is not completely understood. In the present study, we demonstrated that H89 and PKI, selective inhibitors of cAMP dependent protein kinase (PKA), concentration-dependently inhibited Abeta production and soluble APP secretion in cells stably transfected with human APP. Concurrent with these effects, H89 also attenuated the accumulation of carboxyl-terminal fragments of APP, assessed by Western blot. In addition, PKA inhibitor (H89) abolished the maturation of APP in these cells. Results: Direct administration of H89 into brain of transgenic mice overexpressing human APP inhibited Abeta production in hippocampal region. Conclusions: Our data suggests that PKA plays an important role in the maturation of APP and APP processing in HEK293 cells.