The class of drugs used in the experiment consisted ofinhibitors targeted to the epidermal growth factor receptor (EGFR), which isover-expressed in a variety of cancers, specifically a subset of lung cancers.The research revealed that EGFR represents what the team called a "preferredtarget" for treating memory loss associated with the amyloid-beta plaques thatbuild up in the brains of Alzheimer's patients.
Dr. Yi Zhong of Cold Spring Harbor Laboratory (CSHL) led thestudies, which followed previous work in which he and his colleagues hadexamined amyloid beta-associated memory loss in fruit flies with brain cellsexpressing the amyloid-beta-42 peptide (a version of amyloid beta that iscomposed of 42 amino acids and appears in Alzheimer's plaques). The fruitflies, which manifest amyloid beta-42 as a result of a human gene inserted intheir gene, tend to suffer memory issues similar to those that present in humanAlzheimer's. This latest research suggest that the signaling within cells thatis induced by the activation of EGFR plays a role in the pathology involved inamyloid beta-associated memory loss in patients suffering from Alzheimer's.
In the latest experiments, Zhong and his team demonstratethat increased activation of EGFRs in brain cells led to worsening memory lossin amyloid beta-42 fruit fly models of Alzheimer's. The team then dosed theflies with two anti-cancer EGFR inhibitors, erlotinib and gefitinib, approvedanti-cancer treatments that block the EGFR receptor and can prevent itsactivation. The inhibitors reversed memory loss, results that were also seen inmouse models of the disease (also based on the amyloid beta-42 gene).
Given the questions that still exist about the pathology ofAlzheimer's, a specific mechanism of action could not be nailed down withrelation to the experiments, but the evidence implies that the reversal ofmemory loss is the result of clumps of beta-amyloid proteins being blocked fromattaching to the EGF receptor, or the prevention of phosphate groups fromattaching to the receptor. Regardless, it still prevents the EGFR intracellularsignaling cascade from being initiated.
The CSHL research team also tested the drug treatments onmiddle-aged mice with advanced memory loss. The mice were tested over 18 days,a period of time roughly six weeks shorter than the dosing period that wasoriginally proven to be effective.
"Eighteen days—the shortest dosing period we tested—wassufficient to reverse loss in these mice, although we should note that theseanimals had few morphological changes in the brain despite their severe memoryloss when treatment began," said Zhong in a press release.
The potential of EGFR as a druggable target for Alzheimer'streatment was corroborated in a parallel but separate undertaking by Zhong'sassociates. Collaborators in China screened roughly 2,000 synthetic compoundsfor activity against amyloid beta-induced memory loss in fruit fly models ofAlzheimer's. Of those, 45 showed positive results after two months of treatmentin the models, and nine were tested in mouse models, four of which displayedpositive results after two months.
"We were amazed to find that three of these compounds—designatedJKF-006, JKF-011 and JKF-027—not only showed effective results in rescuingmemory loss in the mice, but also, in test tubes, prevented amyloid beta-42from activating human EGFR," noted Zhong.
"We have tested a number of other chemical compounds thathave been identified through our behavior screening. And for those compounds,they have a property that's very interesting in the sense that they onlyinhibit a-beta peptide-induced activation of EGFR, but it cannot inhibit EGF,naturally induced activation of EGFR," Zhong adds. "Therefore those compoundswill have much less side effects as they're developed for treatment forcancers."
Zhong says it would be his dream to bring the compounds toclinical trials, noting that they are talking to companies interested indeveloping the compounds.
In terms of the next step for the research, Zhong says theywill be pursuing several different avenues as they move forward. Though thismost recent research has confirmed that amyloid beta is capable of activatingEGFR, and that the activation is linked to memory loss, the team will beworking to figure out the mechanics of exactly how amyloid beta is capable ofthe activation. The team will also pursue the question of how the compoundsthat were identified were capable of specifically inhibitingamyloid-beta-induced activation of EGFR while not inhibiting naturallyoccurring EGFR activation.
"We think there are several possibilities. Why is it thosecompounds were able to bind with specific spaces for the a-beta peptides?A-beta peptides are able to form a range of oligomers, and it was thought thatsome of those oligomers are toxic, not related to the memory loss. So we arehoping that we can identify how those compounds interact with those specifictoxic oligomers of a-beta peptides and to gain more insights into how thisinhibition, or how this rescue of memory, through this EGFR pathway happens,"says Zhong.
"Secondly, the EGFR activation, the normal activation ofEGFR receptor leading to memory loss, is also not understood very well. So farall the evidence supports, not only in the mouse but also in Drosophila, activation of EGFR througha-beta peptides correlated very well with the memory loss … and blocking thisactivation will lead to rescue of the memory loss," Zhong continues. "Yet wedon't know how this activation really caused the memory loss, so we are alsoworking on this part. We are hoping with those understandings, we will be ableto not only enable us to gain insight into these mechanisms, but also providefurther tools or avenue for developing some novel treatment."
In addition to Zhong, the paper's authors include Lei Wang,Hsueh-cheng Chiang, Wenjuan Wu, Bin Liang, Zuolei Xie, Xingsheng Yao, Weiwei Maand Shuwen Du. Funding for the study came from grants from CSHL, Dart Neuroscience, the Ministry of Science and Technology of Chinaand the Tsinghua-Yue-Yuen Medical Sciences Fund.