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

Abstract

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). Here we demonstrate 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.

• Authors: Bing Gong, Ottavio V Vitolo, Fabrizio Trinchese, Shumin Liu, Michael Shelanski, Ottavio Arancio
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 11 Pg. 1624-34 (Dec 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15578094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Protein Precursor
• Cyclic AMP Response Element-Binding Protein
• Membrane Proteins
• PSEN1 protein, human
• Phosphodiesterase Inhibitors
• Presenilin-1
• Rolipram

Topics

• Alzheimer Disease (drug therapy, physiopathology)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Cognition (drug effects, physiology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Disease Models, Animal
• Hippocampus (cytology, metabolism)
• Humans
• In Vitro Techniques
• Learning (drug effects, physiology)
• Long-Term Potentiation (drug effects)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Transgenic
• Phosphodiesterase Inhibitors (pharmacology, therapeutic use)
• Presenilin-1
• Rolipram (pharmacology, therapeutic use)
• Synaptic Transmission (drug effects, physiology)