Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
Bing Gong, … , Michael Shelanski, Ottavio Arancio
Bing Gong, … , Michael Shelanski, Ottavio Arancio
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1624-1634. https://doi.org/10.1172/JCI22831.
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Article Neuroscience

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 β-peptide 1–42 (Aβ42). 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 Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels.

Authors

Bing Gong, Ottavio V. Vitolo, Fabrizio Trinchese, Shumin Liu, Michael Shelanski, Ottavio Arancio

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Rolipram injections improve contextual conditioning performance both in ...
Rolipram injections improve contextual conditioning performance both in 3-month-old APP/PS1 mice and in 6-month-old double-transgenic mice that had received injections for 3 weeks at the age of 3 months. (A) Three-month-old APP/PS1 and WT littermates treated with rolipram or vehicle 30 minutes prior to testing show no difference in immediate freezing in the training chamber [F(1, 46) = 0.14, P > 0.05]. (B) Three-month-old vehicle-treated APP/PS1 mice show reduced freezing responses compared with vehicle-treated WT littermates during contextual fear conditioning performed 24 hours after training. Injection of rolipram the day before ameliorates the deficit in freezing responses in APP/PS1 mice. Rolipram has no effect on the freezing responses in WT mice [F(1, 46) = 10.57, P < 0.01]. (C) Three-month-old APP/PS1 and WT littermates treated with rolipram or vehicle show similar freezing during cued conditioning [both in the pre-CS group, F(1, 46) = 0.57, P > 0.05, and in the CS group, F(1, 46) = 0.32, P > 0.05]. (D) Six-month-old APP/PS1 and WT littermates previously treated with daily injections of rolipram or vehicle show no difference in immediate freezing in the training chamber [F(1, 47) = 0.79, P > 0.05]. (E) Contextual fear conditioning performed 24 hours after training shows a reduction in freezing responses in 6-month-old APP/PS1 mice pretreated with vehicle compared with that of WT littermates previously treated with vehicle. Pretreatment with rolipram ameliorates the deficit in freezing responses in APP/PS1 mice. Rolipram has no effect on the freezing responses in WT mice [F(1, 47) = 6.68, P < 0.05]. (F) Six-month-old APP/PS1 and WT littermates previously treated with rolipram or vehicle show similar freezing during cued conditioning [both in the pre-CS group, F(1, 47) = 0.07, P > 0.05, and in the CS group, F(1, 47) = 0.34, P > 0.05].