Inhibition of Abeta production and APP maturation by a specific PKA inhibitor.
Alzheimer's disease is characterized pathologically by extracellular amyloid beta protein (Abeta) deposition in the brain. The Abeta peptide, a 39-42 amino acid fragment, is derived from defined proteolysis of the amyloid precursor protein (APP) [Glenner et al., Appl. Pathol. 2 (1984) 357-369; Selkoe, Neuron 6 (1991) 487-498] and is the primary component of senile plaques. Although it is known that intracellular APP is subjected to posttranslational modification, the molecular mechanism that regulates the APP processing is not completely clear. In the present study, we demonstrates that H89, a specific inhibitor for cAMP dependent protein kinase A (PKA), inhibits Abeta production and APP secretion in a dose dependent manner in cells stably transfected with human APP bearing a 'Swedish mutation'. Concurrent with the effect, H89 inhibits C-terminal fragment of the APP. We also found that the PKA inhibitor abolishes the mature form of intracellular APP and accumulates the immature form. Finally, direct administration of H89 into brains of transgenic mice overexpressing human APP shows that the compound inhibits Abeta production in the hippocampal region. Our data suggests that PKA plays an important role in the maturation of APP associated with APP processing.
Su
Yuan
Y
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Ryder
John
J
Ni
Binhui
B
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D013449:Sulfonamides
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide