Scientists have made the unexpected discovery that two marketed anticancer drugs can dramatically restore memory in animal models of Alzheimer’s disease (AD), and may feasibly help hold back or even reverse memory loss in human AD patients.
The discovery, by researchers at Cold Spring Harbor Laboratory (CSHL) and Tsinghua University in Beijing (China), was based on studies in a fruit fly model of AD that expresses Aβ42. Yi Zhong, Ph.D., and colleagues found that Aβ42 directly activates EGFR in the brain, and that treating the AD model fruit flies with either of the EGFR inhibitors gefitinib or erlotinib reversed the memory loss that is characteristic of their AD phenotype.
Subsequent studies in an Aβ42-expressing mouse model of AD supported the findings, and demonstrated that EGFR activation by Aβ42 was directly linked with memory deficits. Again, gefitinib therapy completely reversed memory loss in these animals, even at drug concentrations that were much lower than those used to treat tumors. In fact, just 18 days of gefitinib therapy (the shortest period of treatment evaluated) was enough to rescue memory loss in eight-month old AD animals, which typically exhibit profound memory loss but have yet to develop morphological changes in the brain.
Encouragingly, when the investigators carried out a behavior screen in the AD fruit flies to test a library of 2,000 protein kinase inhibitors, they identified another three compounds that improved memory both in the flies and also in the mouse model even after just two months of treatment.
Although the team admits the mechanism by which Aβ42 leads to increased activation of EGFR isn’t yet known, but in vitro studies did confirm that the EGFR activation was caused by oligomeric, rather than monomeric, Aβ42, and that the peptide bound directly to EGFR. Interestingly, prior work has demonstrated that Aβ oligomers are capable of disrupting long-term synaptic plasticity and the downstream signaling pathways of EGFR, such as PI3-kinase and Ras, which are important in regulating long-term synaptic plasticity.
Reporting their findings in PNAS, the data of Yi Zhong, et al., support the hypothesis that EGFR functions as a cell membrane receptor of Aβ peptides, and that the Aβ oligomer-induced activation of EGFR plays a critical role in leading to memory loss. “The current work suggests that EGFR is an important factor that mediates Aβ42 toxicity, and inhibition of oligomeric Aβ42-induced EGFR activation is an effective way to treat Aβ42-induced memory loss ... It would be of interest to see further effects of EGFR inhibitors as well as behaviorally screened chemicals in treatments of AD patients.”