In experiments with a protein called Ephexin5 that appears to be elevated in the brain cells of Alzheimer’s disease patients and mouse models of the disease, researchers say removing it prevents animals from developing Alzheimer’s characteristic memory losses. In a report on the studies, published in The Journal of Clinical Investigation, the researchers say the findings could eventually advance development of drugs that target Ephexin5 to prevent or treat symptoms of the disorder.
The work with Ephexin5 grew out of a paradox about one of Alzheimer’s disease’s defining features, the development of thick plaques in the brain composed of a protein called amyloid beta. Stemming the production of this protein is currently the major focus of efforts to develop new Alzheimer’s treatments, but it isn’t the amount of amyloid beta in patients’ brains that correlates best with the severity of symptoms; rather, it’s the loss of so-called excitatory synapses, a type of cellular structure forged between two brain cells.
Although it’s not clear how amyloid beta and excitatory synapse loss are connected, researchers showed several years ago that Alzheimer’s patients have decreased brain levels of a protein called EphB2. Ephexin5 is a protein regulated by EphB2 and thought to be responsible for inhibiting the development of dendritic spines, small protrusions on the ends of nerve cells that are the location for most excitatory synapses.
In this study, the researchers used genetic engineering techniques that knocked out the gene that makes Ephexin5, thereby developing mouse Alzheimer’s disease models whose brain cells could not produce the protein. Although the animals still developed the characteristic Alzheimer’s amyloid plaques, they didn’t lose excitatory synapses, retaining the same number as healthy animals as they aged.
To see whether this retention of excitatory synapses in turn affected behavior related to memory tasks, the researchers trained healthy mice, mouse models of Alzheimer’s and Alzheimer’s models genetically engineered to lack Ephexin5 in two learning tasks: one that involved the ability to distinguish objects that had moved upon subsequent visits to the same chamber, and another that involved the ability to avoid chambers where they’d previously received a small electric shock.
While the typical Alzheimer’s disease model mice appeared unable to remember the moved objects or the shocks, the Alzheimer’s animals genetically engineered to be Ephexin5-free performed as well as healthy animals on the two tasks.
To better reflect the human scenario, in which the brain is exposed to amyloid beta for some time, probably decades, before any treatments might be administered, the researchers raised mouse models for Alzheimer’s disease into adulthood — allowing their brains to be exposed to excess amyloid beta for weeks — before injecting their brains with a short piece of genetic material that shut down Ephexin5 production. These mice performed just as well on the memory tasks as the healthy mice and those genetically engineered to produce no Ephexin5.
Together, these results suggest that too much Ephexin5 triggered by amyloid beta and reduced EphB2 signaling might be the reason why Alzheimer’s disease patients gradually lose their excitatory synapses, leading to memory loss — and that shutting down Ephexin5 production could slow or halt the disease.
Paper: “Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice”
Reprinted from materials provided by Johns Hopkins.