In Elderly

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, Johns Hopkins researchers say that 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 that the findings could eventually advance development of drugs that target Ephexin5 to prevent or treat symptoms of the disorder.

‘Ephexin5 is a tantalizing pharmaceutical target because in otherwise healthy adults, there’s very little present in the brain,’ explained Gabrielle L Sell, a graduate student at the Johns Hopkins University School of Medicine.

‘That means shutting off Ephexin5 should carry very few side-effects,’ added Sell, who works with Seth S Margolis, PhD, Assistant Professor of Biological Chemistry and Neuroscience.

Their 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, explain Sell and Margolis, 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 from the University of California, San Francisco, showed several years ago that Alzheimer’s patients have decreased brain levels of a protein called EphB2. Margolis and his colleagues have focused on Ephexin5, 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.

Curious about whether Ephexin5 might also play an important role in Alzheimer’s disease symptoms, Margolis, Sell and Thomas B. Schaffer, also a graduate student in Margolis’ lab, first investigated whether this protein might be poorly regulated in Alzheimer’s animal models and patients.

The researchers discovered that when they added amyloid beta to healthy mouse brain cells growing in petri dishes, these cells began overproducing Ephexin5. Additionally, when they injected the brains of healthy mice with amyloid beta, cells there also began overproducing Ephexin5 — both clues that the protein that makes Alzheimer’s characteristic plaques appears to trigger an increase in brain cells’ production of Ephexin5 of between one- and 2.5-fold.

When the researchers examined preserved brain tissues isolated from Alzheimer’s patients during autopsies, they also found similarly high levels of Ephexin5. Additionally, they found elevated levels of Ephexin5 in mice genetically engineered to overproduce amyloid beta, and that show memory deficits similar to those with human Alzheimer’s disease, further confirming that excess Ephexin5 is associated with this disease.

Armed with what they called this wealth of evidence that brain cells produce too much Ephexin5 when Alzheimer’s disease linked to amyloid beta is present, the researchers then investigated whether reducing Ephexin5 might prevent Alzheimer’s deficits.

Using genetic engineering techniques that knocked out the gene that makes Ephexin5, the researchers developed 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.

The team is currently investigating whether drugs currently in clinical trials for Alzheimer’s disease could be exerting effects on Ephexin5 and how brain cells naturally regulate Ephexin5.

‘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,’ Margolis said.

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