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Morphing brain DNA hints at a whole new way to treat Alzheimer’s

Morphing brain DNA hints at a whole new way to treat Alzheimer’s:

Amyloid protein in Alzheimer's disease.
People with Alzheimer’s disease get a build up of a protein in the brain called beta-amyloid.

 By Alice Klein

Brain cells are reshuffling their own DNA. The finding may explain how Alzheimer’s disease develops and pave the way for new treatments using existing HIV drugs.
Most drugs for treating Alzheimer’s disease are designed to clear out clumps of beta-amyloid protein that build up in the brain of people with the condition. But they have had disappointing outcomes in clinical trials so far.
While studying the gene responsible for making beta-amyloid – called APP – Jerold Chun at Sanford Burnham Prebys Medical Discovery Institute in California and his colleagues discovered something strange. The gene appeared to be able to reshuffle its DNA, allowing it to take thousands of different forms.
The team found about 10 times more variants of the APP gene in brain cells from people with Alzheimer’s disease than without. These different forms were able to produce a range of toxic proteins in addition to beta-amyloid.
The finding may explain why Alzheimer’s drugs that specifically target beta-amyloid have had limited success, says Chun. “They may be missing thousands of other toxic products that are a bit different or maybe very different,” he says.

Shapeshifting gene

At the moment, it’s unclear why the APP gene is able to morph into different forms. In healthy people, it may give the brain greater flexibility by letting it produce a wider repertoire of signaling proteins, says Chun.
We also don’t know why the gene seems to shapeshift more in the brains of people with Alzheimer’s disease, says Chun. So far, his team’s research suggests that it is linked to the activity of a group of enzymes called reverse transcriptases.
The same enzymes are already well-known in the context of HIV, as they are responsible for letting the virus insert itself in infected people’s DNA. It’s possible that existing HIV drugs that block these enzymes  – called reverse transcriptase inhibitors – may also be useful for treating Alzheimer’s disease, says Chun.
This idea is supported by the observation that elderly HIV patients who have been on long-term treatment with reverse transcriptase inhibitors seem rarely to develop Alzheimer’s disease. However, clinical trials will be needed to prove it, says Chun.
His team is currently testing the effectiveness of already-available reverse transcriptase inhibitors for HIV in mouse models of Alzheimer’s disease, as well as planning possible future trials in humans. “The great thing about these drugs is that many of them have been used in HIV patients for decades, so we already know they’re safe,” he says.

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