Mice with Alzheimer’s who are unable to produce the protein Ephexin5 have no memory problems, despite having brains littered with the amyloid beta protein that has been linked to the disease, a study reports.
The finding prompted Johns Hopkins University researchers to conclude that blocking the protein, which is found in excess in the brains of Alzheimer’s patients, may be a way to treat the disease.
It also may explain why levels of amyloid beta in the brain do not correlate with the severity of Alzheimer’s symptoms. Many scientists believe overproduction of amyloid beta is responsible for the development of the disease.
“Ephexin5 is a tantalizing pharmaceutical target because, in otherwise healthy adults, there’s very little present in the brain,” Gabrielle L. Sell, a graduate student at the Johns Hopkins University School of Medicine, and first author of the study, said in a press release. “That means shutting off Ephexin5 should carry very few side effects.”
The research team started pondering Ephexin5’s role when other researchers showed that the brains of Alzheimer’s patients have high levels of a factor called EphB2.
EphB2 controls Ephexin5. Earlier research suggests EphB2 reduces the number of dendritic spines — or tiny protrusions of nerve cells — that scientists believe hold the majority of the synapses that disappear in Alzheimer’s. Synapses are involved in the transmission of nerve signals.
The team started by exploring the protein in lab-grown cells. Adding amyloid beta to lab-dish cells from healthy mice prompted the cells to produce Ephexin5. Researchers saw the same thing when they injected amyloid beta into the brains of healthy mice. Brains of deceased Alzheimer’s patients also contained higher levels of Ephexin5.
Researchers then turned to mouse models of Alzheimer’s that were engineered to produce excessive amounts of amyloid beta. The mice also had high Ephexin5 brain levels, along with the memory problems that characterize Alzheimer’s.
Up to that point, the evidence the team had collected indicated that the protein might be part of Alzheimer’s processes, but this did not prove that it causes cognitive decline.
To test the idea, the team manipulated Alzheimer’s mice — which produce plenty of amyloid beta — to deprive them of Ephexin5. They then tested the memory of healthy mice, Alzheimer’s mice, and Ephexin5-lacking Alzheimer’s mice.
They noted no differences in memory between mice lacking Ephexin5 and normal mice.
But since these mice lacked the protein from birth, researchers did another test. First they bred Alzheimer’s mice to adult age. This was intended to mirror the human scenario, in which patients typically accumulate amyloid beta for decades before memory symptoms start showing.
The team then used another molecular tool to shut down Ephexin5 production. They found that mice whose Ephexin5 was blocked at an older age did as well on memory tests as healthy mice.
“This study gives us some hope that moving beyond efforts to interrupt amyloid-beta pathways, and targeting pathways for synapse formation, will give us potent therapies for this devastating disease,” said Seth S. Margolis, PhD, assistant professor of biological chemistry and neuroscience, and the senior author of the study.
Since most treatment development approaches focus on lowering amyloid beta levels in the brain, the team is now examining if drugs that are currently in clinical trials can impact Ephexin5. They are also trying to learn how the protein is controlled in a healthy brain.
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