Alzheimer’s disease is characterized pathologically by extracellular amyloid β protein (Aβ) deposition in the brain. The AL peptide, a 39-42 amino acid fragment, is derived from defined proteolysis of the amyloid precursor protein (APP) 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, they demonstrate that H89, a specific inhibitor for cAMP dependent protein kinase A (PKA), inhibits AL 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. They 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 AL production in the hippocampal region. Our data suggests that PKA plays an important role in the maturation of APP associated with APP processing.