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Late-night serendipity yields new insight Into Alzheimer’s disease

It was 2:30 on a winter morning several years ago at the National Institutes of Health outside of Washington, D.C. when Annelise Barron, PhD, a professor of bioengineering, spotted something odd. She’d been staring at a grant application that included a description of the structure of amyloid beta, a molecule associated with Alzheimer’s disease, when her graduate student sent her a similar description of cathelicidin, an immune-system compound Barron and her lab had long been studying.

In Alzheimer’s, amyloid beta accumulates on and weakens the connections between neurons in the brain. But as Barron glanced back and forth between the structures of amyloid beta and cathelicidin, she realized the two molecules — both peptides, or short chains of amino acids — looked like they would fit together hand in glove. If so, maybe Alzheimer’s wasn’t caused by accumulating amyloid beta, but rather by an imbalance between amyloid beta and cathelicidin, a kind of disturbance in the yin and yang of the brain.

Thus began what Barron says is “the most exciting intellectual journey I’ve ever been on.”

The first fruits of that journey are appearing in the Journal of Alzheimer’s Disease, in which Barron and colleagues from Italy and Canada explore the interactions between amyloid beta and cathelicidin for the first time.

The team showed that the two peptides do bind tightly together, and they found that amyloid beta did not form into the plaques and fibrils characteristic of Alzheimer’s disease when in the presence of cathelicidin.

But what may be most exciting is what the combination of amyloid beta and cathelicidin do to cells — or rather what they don’t do.

Like amyloid beta, cathelicidin is toxic to neurons — cathelicidin is key to cleaning up dysfunctional cells, such as infected cells or cancer cells — so it would make sense if putting them together was even more toxic. In fact, the opposite happens: lab tests showed that although they were individually toxic to cells, the combination of amyloid beta and cathelicidin in equal measure was not toxic. Instead, the results indicate the two compounds form a stable non-toxic complex.

In the long run, Barron says she hopes the research could lead to new, less expensive drugs to treat Alzheimer’s, but she emphasizes the research is still in its very earliest stages. The next step will be to take the experiments from cells gathered in a dish to experiments in mice. Those experiments are already under way, and the early results seem to support the team's hypothesis, Barron said. “The mice will tell us if we’re right,” she said, or at least right enough to move on to humans.

Previously: New study hints at why infamous gene variant increases odds of developing Alzheimer's disease and Alzheimer's puzzle pieces are coming together
Photo by LeoNeoBoy

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