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Untangling the Story of Tau

Two unmistakable signs of Alzheimer's disease are the so-called plaques and tangles in a victim's brain. Scientists have a good handle on how plaques form. The tangles have been more of a mystery--until now, that is. A new report shows that an abnormally shortened version of a common protein triggers the distinctive tangles.

In contrast to Alzheimer's plaques, which are essentially jumbles of a protein called b amyloid piled up in between brain cells, tangles form inside cells. The tangles are made up of a protein called tau, which binds to a cell's scaffolding of microtubules for reasons not yet known. If, somehow, many phosphate molecules get attached to tau, the protein clumps up into tangles that eventually kill the neuron.

In this week's issue of Nature, pathologist Li-Huei Tsai of Harvard Medical School in Boston and her colleagues identify a faulty protein that seems to spur another protein to keep adding phosphates to tau molecules long after it should have stopped. The team was looking for evidence that a protein called p35, which works with a partner called Cdk5 to add phosphates to other proteins, might play a role in Alzheimer's disease. When they examined samples from the brains of patients who had died of Alzheimer's, they found nothing unusual about the p35 levels, but they did find high levels of a truncated version called p25. Brains of people who had died of other causes, including Huntington's disease, had almost no p25.

Curious about what p25 might do, the team churned out extra copies of the protein in cultured cells. High levels of the abnormal protein seem to change the behavior of Cdk5. A freshly made p35 molecule attaches to the cell's membrane and is degraded within minutes, ensuring that Cdk5 is turned on only for brief spurts in a cell's perimeter. But when the team stained cells with antibodies to p25, they found the protein throughout the cell; it also persisted up to 10 times longer than its normal cousin. The researchers propose that with p25 in the cell, Cdk5 becomes overactive, adding extra phosphates to tau and other proteins, eventually leading to the tangles.

That explanation is "quite convincing," says Alzheimer researcher Dennis Selkoe of Harvard Medical School. But the researchers do not explain how p35 gets shortened to p25 in the first place, he says. Selkoe speculates that it may have something to do with the b amyloid protein that causes Alzheimer's plaques. He says the damage that b amyloid does to neurons might spark the production of p25, which is known to appear in response to cell stress. Tsai says her team is testing that theory and hopes to have an answer soon.