11 Jan 2008

Lithium is an old and much used psychiatric drug, whose mechanism of action remains murky. Inhibition of the glycogen synthase kinase 3 β (GSK-3β) has been implicated, but lithium inhibits this enzyme only weakly and requires much higher concentrations to block it in vitro than to elicit a therapeutic effect in vivo. Now, work from the lab of Marc Caron at Duke University Medical Center, Durham, North Carolina, shows that lithium can inhibit GSK-3 in vivo, but does so indirectly. It disrupts its signaling through the upstream kinase Akt. Specifically, lithium breaks up a magnesium-dependent association of Akt with the scaffolding protein β-arrestin 2 (β-ARR2). That results in activation of Akt, which then phosphorylates and inhibits GSK-3β.

Published in the January 11 issue of Cell, the work reveals an important target for lithium. The drug is of interest to Alzheimerologists who are themselves studying ways to shut down GSK-3β because it is a major kinase responsible for tau phosphorylation. Inhibitors of GSK-3, including lithium, are being looked at as possible therapeutics (Caccamo et al., 2007).

In addition, the PI3K/Akt/GSK-3β pathway is important for the survival of neurons. In a separate development, a new paper reports that this function may be compromised in cases of familial AD due to presenilin mutations. In the January 9 Journal of Neuroscience, researchers led by Nikolaos Robakis at the Mt. Sinai School of Medicine in New York report that presenilin-1 promotes the survival of embryonic neurons in culture by activating the Akt pathway in a way that is independent of γ-secretase activity. Moreover, the researchers show that FAD mutations abolish this function of presenilin. The results support the idea that inhibiting GSK-3β could be beneficial in AD, and they offer an alternative pathway by which FAD mutations could cause AD via a loss-of-function mechanism (see a recent and extensive ARF discussion of this topic).

In the lithium story, first author Jean-Martin Beaulieu used β-arrestin 2 (βARR2) knockout mice to probe the role of this scaffolding protein in lithium action. βARR2 organizes a signaling complex on G protein-coupled receptors that includes the Akt kinase. The complex does not require G proteins for activity, and thus represents an alternative signaling pathway utilized by GPCRs. Beaulieu and colleagues show that lithium injection into the striatum of mice led to activation of Akt and the subsequent inactivation of GSK-3β kinase. Lithium had no such effect in βARR2 knockout mice, nor did the mice show the expected behavioral effects of lithium treatment. The knockout mice were also refractory to chronic changes in the activity of Akt or GSK-3, and associated expression of the β-catenin gene, upon prolonged lithium treatment.

In-vitro immunoprecipitation studies showed that βARR2 was required to see interaction of Akt with protein phosphatase 2A in a signaling complex. Lithium prevented the association of Akt with βARR2 or Akt and two different subunits of PP2A. A similar effect was seen in vivo. Lithium broke up the complex by competing with magnesium, which was required for the interaction. Importantly, all these effects occurred at concentrations of lithium that are attained therapeutically. The effects of lithium appeared specific to the GPCR-mediated regulation of the Akt pathway, and the drug did not interfere with other functions of either βARR2 or G protein-dependent receptor signaling. The results indicate that lithium may not generally inhibit the pathway, but instead offers a means of precisely targeting selective GPCR functions that rely on arrestin-containing signaling complexes.

What has all this got to do with AD? The same Akt/GSK-3β pathway hit by lithium keeps developing neurons alive, and has been shown to be under the control of the γ-secretase subunit presenilin in non-neuronal cells (see ARF related news story; Baki et al., 2004; Uemura et al., 2007). New data from Lia Baki in the Robakis lab, together with Rachael Neve of McLean Hospital and Harvard University in Belmont, Massachusetts, show that the ability of presenilin-1 to promote the activity of the Akt survival pathway in embryonic neurons is abolished by presenilin mutations that cause familial AD.

In that study, the researchers cultured embryonic neurons from PS1 knockout mice and found that their maturation in vitro coincided with a decrease in Akt activity, an increase in GSK-3, increased proapoptotic caspase 3 activity, and dendrite retraction. When they expressed wild-type PS1, or constitutively active Akt, they observed that restoration of PI3K signaling turned off caspase 3 and stopped dendrite retraction. γ-secretase inhibitors did not stop this effect of PS1, but a PI3K inhibitor did. Interestingly, any one of several different FAD mutations prevented PS1 from supporting PI3/Akt signaling and preventing apoptosis.

“Our data indicate that the neuroprotective role of PS1 depends on its ability to promote the PI3K/Akt signaling and suggest a mechanism by which PS1 FAD mutations contribute to neurodegeneration.” The data are consistent with a loss-of-function model for presenilin action, and a potential role for inhibitors of GSK-3β, whether lithium or other compounds, in treating familial disease.—Pat McCaffrey

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References

Webinar Citations

1. Presenilin Loss of Function—Plan B for AD? 9 Mar 2007

News Citations

1. Presenilins Work Overtime to Control Akt, Tau, and Aβ—n-3 Fatty Acids Aid and Abet 25 Jul 2005

Paper Citations

1. Caccamo A, Oddo S, Tran LX, Laferla FM. Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol. 2007 May;170(5):1669-75. PubMed.
2. Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gama-Sosa M, Neve R, Robakis NK. PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J. 2004 Jul 7;23(13):2586-96. PubMed.
3. Uemura K, Kuzuya A, Shimozono Y, Aoyagi N, Ando K, Shimohama S, Kinoshita A. GSK3beta activity modifies the localization and function of presenilin 1. J Biol Chem. 2007 May 25;282(21):15823-32. PubMed.

Further Reading

News

1. Presenilins Work Overtime to Control Akt, Tau, and Aβ—n-3 Fatty Acids Aid and Abet 25 Jul 2005