Gleevec, the cancer "wonder drug" that has proven effective for gastrointestinal stromal tumors might also be useful for Alzheimer's patients, if only one could deliver it to the brain effectively, according to a paper in this week's early online edition of PNAS.
Principal author Paul Greengard, and colleagues from The Rockefeller University and the Memorial Sloan-Kettering Center, both in New York, report that the kinase inhibitor, whose chemical name is imatinib mesylate, reduces γ-secretase cleavage of Aβ precursor protein (AβPP) without affecting Notch processing. The latter is fortuitous, as potential interference with Notch signaling and other pathways is one of the obstacles impeding the search for γ-secretase-targeted therapeutics (see ARF related news story), ARF news story, and scroll to Shearman in Titisee conference report).
Gleevec inhibits Abl, and several other tyrosine kinases, by blocking the enzymes' ATP binding site. Greengard and colleagues had previously shown that in a cell-free system consisting of mouse N2a neuroblastoma membranes, the γ-secretase cleavage of AβPP is ATP dependent. This prompted joint first authors William Netzer, Fei Dou, and Dongming Cai to try blocking the ATP-dependent step in the production of Aβ. When the authors added Gleevec to either the cell-free system or to N2a cells themselves, production of Aβ decreased by 50 percent. In contrast, the quantity of Notch's intracellular domain produced by the N2a cells remained constant.
The authors found that Gleevec was primarily, if not exclusively, affecting the γ-secretase step of Aβ production because it had no effect on the level of the β-secretase-generated C-terminal fragment (CTF) of AβPP. In addition, when they added Gleevec to N2a cells expressing this CTF, Aβ production was still blocked, though not as robustly as in cells expressing full-length AβPP.
When Netzer and colleagues added the kinase inhibitor to cultured primary neurons, they found a similar effect. Five μM Gleevec inhibited Aβ production by 75 percent, while the similar ATP site blocker PD173955 worked even better, inhibiting by 80 percent at a fivefold lower dose. In vivo, the kinase inhibitors were also effective. When the authors administered as little as 0.2 mg/Kg of either drug into the brains of adult albino guinea pigs, cortical levels of Aβ dropped by over half, while the levels of the β-secretase CTF rose by as much as fourfold. These results, which were statistically significant, suggest that γ-secretase cleavage can be effectively halted in vivo.
How Gleevec works in this context is uncertain. The authors show that it is just as effective at inhibiting γ-secretase in Abl-negative cells, and suggest that other tyrosine protein kinases, such as platelet-derived growth factor receptor (PDGFR) or Src kinase, may be involved. Intriguingly, Tommaso Russo's group has just reported that PDGFR and Src kinase may play a role in Aβ production (see Gianni et al., 2003).
Gleevec has FDA approval, and the authors write that "the safety of Gleevec, demonstrated by its successful application to […] tumors, and its inability to inhibit Notch-1 cleavage by γ-secretase, make this class of compounds attractive as potentially safe, Aβ-lowering drugs." If, that is, ways can be found to get them across the blood-brain barrier.—Tom Fagan