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
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
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."
Cold Spring Harbor Laboratory