Among its many reputed transgressions, amyloid-β is suspected of interfering with synaptic function from the earliest stages of Alzheimer disease (see ARF related news story). A study published in the December issue of the Journal of Clinical Investigation offers up a candidate synaptic bodyguard. Ottavio Arancio and colleagues at the Taub Institute at Columbia University, the Nathan Kline Institute, and the New York University School of Medicine, all in New York state, report that the drug rolipram protects synaptic function and memory in AD transgenic mice, apparently by boosting cAMP and, hence, CREB-mediated gene transcription.

A recent study by Arancio and colleagues showed that long-term potentiation (LTP)—the synaptic remodeling believed to underlie learning and memory—was vulnerable to Aβ, specifically through Aβ's inhibition of the pathway trekked by cAMP, cAMP-dependent protein kinase (PKA), and cAMP regulatory element binding protein (CREB) (see ARF related news story). There is evidence to support a model whereby the cAMP/PKA/CREB pathway regulates memory by controlling the expression of proteins that promote synaptic plasticity (see, for example, Navakkode et al., 2004).

Perhaps, then, compounds that upregulate this pathway would be able to override or compensate for Aβ's inhibition of LTP, and, if the model is correct, improve synaptic plasticity and protect learning and memory. Indeed, Arancio's group has also found that the drug rolipram, by inhibiting one of the numerous phosphodiesterases (PDEs) that help regulate cAMP, is able to restore the cAMP/PKA/CREB pathway and LTP. Rolipram is approved for use in depression and is being studied in other conditions such as multiple sclerosis and stroke, but it is not a newcomer to the memory preservation challenge. Along with other PDE4 inhibitors (including caffeine, many will be happy to know), the drug has been shown to enhance memory and cognition in a number of aging, disease, and synaptic dysfunction models.

In their current study, Arancio, first author Bing Gong, and colleagues examined the effects of rolipram in mice carrying both APP (K670N, M671L) and presenilin (M146L) mutations. By six months of age, APP/PS1 mice have developed deficits in basal synaptic transmission and LTP, along with learning and memory impairments (Trinchese et al., 2004). In an initial round of experiments, examining the short-term effects of rolipram on younger mice, the researchers worked first on hippocampal slices from three-month-old APP/PS1 and wild-type mice. Consistent with previous research, Gong and colleagues found that basal synaptic transmission was not yet affected in the AD transgenic mice, though LTP was reduced by about half. However, when bathed with rolipram, the neural circuits in APP/PS1 slices achieved levels of synaptic potentiation equivalent to those of wild-type slices.

Select benefits were also seen in short-term behavioral experiments in the three-month-old mice. Gong and colleagues found that a single dose of rolipram restored fear conditioning learning in the APP/PS1 mice to wild-type levels, though it did not improve performance on a radial arm water maze that measures spatial working memory.

A second round of experiments gave even more encouraging results. The researchers treated three-month-old mice with rolipram for three weeks, then waited 9-11 weeks to assess synaptic function and memory. By this age, APP/PS1 animals have developed deficits in basal synaptic transmission as well as LTP, but both these deficits were absent in mice given rolipram several months earlier.

As in the acute administration experiments in three-month-olds, the long-term rolipram treatment rescued fear conditioning in the older APP/PS1 mice, but the drug also protected spatial working memory, as judged by radial arm maze experiments. Most impressively, on several measures of long-term memory in the Morris water maze, the scores of APP/PS1 mice given rolipram were significantly higher than those of untreated mice and comparable to the performance of wild-type mice.

Finally, Gong and colleagues probed some of the changes that might underlie the long-term benefits of rolipram on synaptic function and cognition. They found that the older APP/PS1 mice previously treated with rolipram had hippocampal levels of CREB phosphorylation (as measured by Western blot) similar to wild-type mice, and significantly higher than transgenic mice that did not receive the drug. Similar results were obtained with immunohistochemical analysis of phospho-CREB levels.

"In considering possible applications of rolipram and PDE4 inhibitors for the treatment of AD, it is significant that the observed trophic effects are not limited to the initial phase of synaptic and behavioral changes in the young animals and that they are actually proportionally larger in the older mice. This widens the possible therapeutic window of this class of compounds, not limiting it to the initial phases of the disease," write the authors.

The drug seems to have had no direct effect on Aβ—Aβ40 and -42 levels were unchanged in the APP/PS1 mice following rolipram administration, as was cortical plaque burden. In light of the fact that CREB-dependent gene expression has been strongly implicated in memory processes, the authors write that, "Given rolipram’s short half-life, it is likely that the persistent improvement in the behavior and synaptic responses of rolipram-treated APP/PS1 animals is due to stabilization of synaptic circuitry via alterations in gene expression." Such stabilization might also be achieved with other agents that increase cAMP levels, according to Gong and colleagues.—Hakon Heimer

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  1. Arancio, first author Bing Gong, and colleagues show evidence that Rolipram improved synaptic and cognitive functions in an Alzheimer mouse model. The cAMP/PKA/CREB pathway controls CREB-dependent gene expression, which is fundamental for neuronal survival, and plasticity involved in memory process—all affected in AD. Several groups have previously reported that abnormal β-amyloid accumulation induces cognitive impairment that parallels disturbances in cAMP signaling, including a decrease in PKA and CREB activation. β amyloid-induced inhibition of the PKA/CREB pathway and long-term potentiation (a cellular model of learning) seem to be rescued by drugs that enhance cAMP signaling (Vitolo et al., 2002). In concurrence with this evidence, we reported in NSF and at the ADRD meeting that stimulation of the PGE2 EP2 receptor, which increases cAMP levels, protected cultured cortical neurons against Aβ toxicity (Echeverria, V and Doré, S. 9th Intl. Conference on Alzheimer’s Disease and Related Disorders. 2004). Rolipram is a selective inhibitor of phosphodiesterase PDE4 and induces an elevation of intracellular cAMP and release of norepinephrine, enhancing central noradrenergic transmission, and suppressing expression of several mediators of inflammation. PDE4 is used to treat leukemia patients. From there we learned that some resistance to treatment with Rolipram can appear, because elevated cAMP levels can induce compensatory upregulation of other PDE families. Some combination therapy with more than one PDE4 inhibitor or use of dual-selective drugs may likely be of benefit in a subset of potentially PDE4-inhibitor-resistant patients and also directed to decrease Aβ levels. It is impressive that Rolipram could have these long-term benefits without decreasing the amyloid burden and Aβ levels. In this respect, it would be interesting to investigate if Rolipram reduces intracellular Aβ accumulation. The risk associated with the use of these PDE4 inhibitors in the elderly as well the advantages with respect to other PDE inhibitors such as caffeine need to be carefully evaluated. However, the benefits in terms of neuroprotection and anti-cancer properties made these kinds of PDE inhibitors promising therapeutic tools.

    References:

    . Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13217-21. PubMed.

References

News Citations

  1. New Orleans: Symposium Probes Why Synapses Are Suffering
  2. Filling in Signaling Steps Between Aβ and Long-Term Potentiation

Paper Citations

  1. . The type IV-specific phosphodiesterase inhibitor rolipram and its effect on hippocampal long-term potentiation and synaptic tagging. J Neurosci. 2004 Sep 1;24(35):7740-4. PubMed.
  2. . Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol. 2004 Jun;55(6):801-14. PubMed.

Further Reading

Primary Papers

  1. . Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004 Dec;114(11):1624-34. PubMed.