Skip to main content
U.S. flag

An official website of the United States government

Inhibition of Aβ production and APP maturation by a specific PKA inhibitor


Year of Publication:
Contact PI Name:
Binhui Ni
Contact PI Affiliation:
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Yuan Su, John Ryder
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:

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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Protein Kinase A (PKA)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Protein Kinase A (PKA) Activity
Brain-beta Amyloid Peptide-Total
Brain-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP)
Soluble Amyloid Precursor Protein (sAPP)
Cell Biology
Cell Viability
Target Engagement (Inhibition Protein Kinase A)
Cell Viability