Anti-cancer EGFR inhibitors effective in reversing memory loss in animal models of Alzheimer's

Cold Spring Harbor LaboratorySep 25 2012

A team of neuroscientists and chemists from the U.S. and China today publish research suggesting that a class of currently used anti-cancer drugs as well as several previously untested synthetic compounds show effectiveness in reversing memory loss in two animal models of Alzheimer's disease.    

CSHL Professor Yi Zhong, Ph.D., who led the research conducted in fruit flies and mice, says he and his colleagues were surprised with their results, which, he stressed, used two independent experimental approaches "the results of which clearly converged."

Specifically, the research converged on what Zhong's team suggests is a "preferred target" for treating memory loss associated with the amyloid-beta (Aβ) plaques seen in advanced Alzheimer's patients. That target is the epidermal growth factor receptor, often called by its acronym, EGFR.

Overexpression of the EGFR is a characteristic feature of certain cancers, notably a subset of lung cancers. Two targeted treatments, erlotinib (Tarceva) and gefitinib (Iressa), can dramatically, albeit transiently, reverse EGFR-positive cancers, by blocking the EGFR receptor and thus preventing its activation.

The newly published research by Zhong's team suggests that the signaling within cells that is induced by EGFR activation also plays a role in the pathology - still poorly understood - involved in Aβ-associated memory loss seen in Alzheimer's patients.

Zhong's team demonstrated that enhanced activation of EGFRs in brain cells exacerbated memory loss in the Aβ-42 fruit fly model of Alzheimer's disease. This led them to dose 3-day-old flies of the same type with the two anti-cancer EGFR inhibitors over a week's time, which was shown in behavioral tests on day 11 to prevent memory loss. The results were then confirmed in mouse models of Alzheimer's, also based on the human Aβ-42 gene.

This was remarkable, but even more so, says Zhong, because of a parallel but independent experimental process that also suggested EGFR as a drug target for Alzheimer's. This parallel process consisted of screening, by Zhong's collaborators in China, of some 2,000 synthetic compounds for activity against Aβ-induced memory loss in model fruit flies. Of these, 45 compounds showed positive results in fruit flies after two months of dosing. Nine of these were selected for testing in mouse models, of which four showed positive results after two months.

A precise mechanism could not be conclusively demonstrated from this and related experiments. Because of the positive results they obtained in reversing memory loss in animal models, the team suggests additional testing with EGFR inhibitors be conducted, as well as testing of "behaviorally screened chemicals in treatments of Alzheimer's patients."