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Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice


Year of Publication:
Contact PI Name:
Daniel L. Alkon
Contact PI Affiliation:
The Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland, USA
Rene Etcheberrigaray, Mathew Tan, Ilse Dewachter, Cuno Kuiperi, Ingrid Van der Auwera, Stefaan Wera, Lixin Qiao, Barry Bank, Thomas J. Nelson, Alan P. Kozikowski, Fred Van Leuven
Primary Reference (PubMED ID):
Funding Source:
Katholieke Universiteit Leuven Research and Development
The Research Foundation-Flanders/Fonds voor Watenschappelijk Onderzoek-Vlaanderen (FWO)
Study Goal and Principal Findings:

Alzheimer’s disease (AD) characteristically presents with early memory loss. Regulation of K channels, calcium homeostasis, and protein kinase C (PKC) activation are molecular events that have been implicated during associative memory which are also altered or defective in AD. PKC is also involved in the processing of the amyloid precursor protein (APP), a central element in AD pathophysiology. In previous studies, we demonstrated that benzolactam (BL), a novel PKC activator, reversed K channels defects and enhanced secretion of APP in AD cells. In this study we present data showing that another PKC activator, bryostatin 1, at subnanomolar concentrations dramatically enhances the secretion of the -secretase product sAPP in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPP and reduced A40 in the brains of APP[V717I] transgenic mice. In a more recently developed AD double-transgenic mouse, bryostatin was effective in reducing both brain A40 and A42. In addition, bryostatin ameliorated the rate of premature death and improved behavioral outcomes. Collectively, these data corroborate PKC and its activation as a potentially important means of ameliorating AD pathophysiology and perhaps cognitive impairment, thus offering a promising target for drug development. Because bryostatin 1 is devoid of tumor-promoting activity and is undergoing numerous clinical studies for cancer treatment in humans, it might be readily tested in patients as a potential therapeutic agent for Alzheimer’s disease.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Protein Kinase C (PKC)
Therapy Type:
Small Molecule
Therapeutic Agent:
Bryostatin 1
Therapeutic Target:
Protein Kinase C (PKC)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported
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
Open Field Test
Morris Water Maze
Soluble Amyloid Precursor Protein alpha (sAPP alpha)
Protein Kinase C (PKC)
Amyloid Precursor Protein (APP)
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP) Metabolites
General Behavior
Body Weight