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Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment


Year of Publication:
Contact PI Name:
Ottavio Arancio
Contact PI Affiliation:
The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA
Bing Gong, Ottavio V. Vitolo, Fabrizio Trinchese, Shumin Liu, Michael Shelanski
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
National Institute on Aging (NIA)
Institute for the Study of Aging (ISOA)
Study Goal and Principal Findings:

Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). This study demonstrates that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Phosphodiesterase Type 4 (PDE4)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported
Animal Model Notes:
APPxPS1 mice for this study were generated by crossing Tg2576 mice ( and PS1(M146V) mice (

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
Radial Arm Water Maze
Morris Water Maze
Contextual Fear Conditioning
beta Amyloid Load
beta Amyloid Deposits
Brain-Formic Acid Soluble beta Amyloid Peptides
cAMP Response Element-Binding Protein (CREB)
phospho-cAMP Response Element-Binding Protein (phospho-CREB)
Extracellular Signal-Regulated Kinase 1/2 (ERK1/2)
phospho-cAMP Response Element-Binding Protein (phospho-CREB)
Long Term Potentiation (LTP)