The widely used psychiatric drug lithium, and other agents that inhibit glycogen synthase kinase-3 (GSK3), have been mentioned as possible Alzheimer's disease therapies for some time, primarily because GSK3 is one of several kinases known to phosphorylate tau. An article in today's Nature reinforces more recent speculation that interfering with GSK3 could also reduce the production of the Aβ peptide, putting before drug developers the tantalizing prospect of hitting two birds (i.e., the two major AD pathologies) with one stone.
The suggestion that GSK3 could be involved in Aβ production stems from the kinase's interaction with presenilins, though there has been no demonstration of direct involvement of GSK3 in presenilin-mediated γ-secretase cleavage of amyloid precursor protein. Last year, Akihiko Takashima's group reported that high doses of the GSK3 inhibitor lithium interfere with in-vitro production of Aβ40 and 42 (Sun et al., 2002). The current report by Peter Klein and associates at the University of Pennsylvania in Philadelphia confirms and extends this finding, showing that more clinically relevant doses of lithium chloride reduce Aβ production from full-length APP in cultured neurons, as well as in the brains of a mouse model transgenic for mutated APP and containing a "knock-in" of a presenilin mutation. Klein and colleagues also identified the target of lithium responsible for this effect, namely GSK3α. The fact that C-terminal fragments of AβPP pile up in the in-vitro models indicates that this effect of lithium occurs before or during the γ-secretase cleavage of AβPP. Inhibitor experiments in AβPP-transgenic CHO cells using kenpaullone (which inhibits GSK and, less strongly, CDKs) and roscovitine (which inhibits CDKs but not GSK), indicated that lithium inhibits Aβ generation via GSK inhibition, not via CDK inhibition.
The researchers provide several lines of evidence to show that it is the GSK3α isoform—and not GSK3β—that facilitates Aβ production. For example, RNAi-mediated depletion of GSK3α, but not β, reduces Aβ production. Conversely, moderate overexpression of the α isoform increases Aβ production.
Unlike most γ-secretase inhibitors, lithium did not inhibit Notch processing by γ-secretase. This would be an important specificity criteria for a drug candidate. The researchers suspect that GSKα might specifically regulate γ-secretase activity toward AβPP, or access of AβPP to the enzyme complex. NSAIDs that modulate γ-secretase activity also do not affect Notch cleavage (see ARF related news story), though they appear to act by a different mechanism.
Lithium targets both the α and β isoforms, making an agent that targets only GSK3α preferable, write the authors. In an accompanying News and Views article, Bart de Strooper of KU Leuven, Belgium, and James Woodgett at Ontario Cancer Institute in Toronto add that GSK inhibition might carry the risk of tumor-causing side effects through the GSK target β-catenin. Lithium itself is not associated with increased risk of cancer, but new, more potent GSK-3 inhibitors might, so it is important to keep that possibility in mind, noted Klein. On the up side, however, de Strooper and Woodgett write that the effective dose of lithium chloride in the present experiments falls within the range of the accepted therapeutic dose for this drug. They write that some Alzheimer's patients might benefit from lithium, but recommend that any potential effect of this drug on dementia be assessed in a clinical trial designed for that purpose, since measuring this outcome in psychiatric patients who currently receive this drug will be difficult.—Hakon Heimer and Gabrielle Strobel