Toxic Tau Of Alzheimer's May Offer A Path To Treatment

Toxic Tau Of Alzheimer's May Offer A Path To Treatment

9:08am Nov 19, 2014
A tangle of protein (green) in this scanning electron micrograph of a brain cell of an Alzheimer's patient lies within the cytoplasm (blue) of the cell. The tangle consists of clumps of a toxic form of tau.
A tangle of protein (green) in this scanning electron micrograph of a brain cell of an Alzheimer's patient lies within the cytoplasm (blue) of the cell. The tangle consists of clumps of a toxic form of tau.
Thomas J. Deerinck / Corbis

After years of setbacks, Alzheimer's researchers are sounding optimistic again. The reason: a brain protein called tau.

At this year's Society for Neuroscience meeting in Washington, D.C., there are more than 100 papers on tau, which is responsible for the tangles that form in the brains of people with Alzheimer's. In the past, tau has received less attention than another protein called amyloid beta, which causes the sticky plaques associated with Alzheimer's.

"Many people focused on amyloid beta for many years," says Julia Gerson, a graduate student in neuroscience at the University of Texas Medical Branch, who presented a paper on tau at the neuroscience meeting. "Now it's coming out that tau might be more important."

"Clearly both are working together, conspiring if you will, to bring down cell functions and cell survival over the years as the disease unfolds," says Dr. Lennart Mucke, a neurologist who directs the Gladstone Institute of Neurological Disease, a research center affiliated with the University of California, San Francisco.

In the past decade, several promising drugs that merely lower amyloid have failed to stop Alzheimer's. Those failures, Mucke says, helped persuade scientists to take a closer look at tau, which has produced some surprising findings.

"Initially it was thought that tau was purely inside brain cells," he says. "But now we recognize that it can actually exist outside of cells and even transfer from one cell to the next."

The idea that tau can spread from cell to cell like an infection suggests a new way to treat Alzheimer's, Mucke says. "If we could figure out how to stop that spread, maybe one could limit the disease to just some brain regions, instead of having it go everywhere."

Some researchers are already trying to interrupt the process, using the immune system to mop up toxic forms of tau. A similar strategy has proved effective for reducing amyloid.

The closer look at tau also revealed that the protein comes in different forms. In its most common form, tau actually helps brain cells function, Gerson says. "But in disease, for various reasons that we don't entirely understand yet, it takes on this other, toxic form," she says.

This toxic tau, known as a tau oligomer, occurs not only in Alzheimer's patients but also in people with traumatic brain injury. In both groups, Gerson says, the protein appears to build up over time and lead to memory problems.

To find out more about this process, Gerson and a team of scientists injected tau oligomers from people with Alzheimer's into the brains of healthy mice. Within a week the mice developed memory problems; tissue samples showed toxic tau throughout the animals' brains. "What we believe is happening is that the toxic form [of tau] induces the healthy form in the brains of these mice to take on that toxic conformation," Gerson says.

The new research suggests that treating Alzheimer's will require drugs that affect both tau and amyloid, and perhaps other factors that are less well understood, Mucke says. That means doctors will need a lot of different tools.

"The problem," he says, "has been that the toolbox was nearly empty." Thanks to the sort of research presented at this year's neuroscience meeting, Mucke says, that toolbox is starting to fill up again.

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Transcript

ROBERT SIEGEL, HOST:

After years of setbacks, scientists are once again optimistic about finding a treatment for Alzheimer's disease. One reason is a better understanding of a substance in the brain called tau. NPR's Jon Hamilton reports from the Society for Neuroscience meeting in Washington, D.C.

JON HAMILTON, BYLINE: The brain of a person with Alzheimer's has abnormalities known as plaques and tangles. Plaques are made of a sticky protein called amyloid. Tangles are made of a different protein, tau. For a long time, scientists argued about whether amyloid or tau was the primary cause of Alzheimer's. Lennart Mucke of the Gladstone Institutes at the University of California, San Francisco says that debate has evolved.

LENNART MUCKE: Clearly, both are working together - in fact, conspiring if you will - to bring down cell functions and cell survival over the years as the disease unfolds in the brains of people with Alzheimer's.

HAMILTON: Which could explain why drugs that just lower amyloid have failed to stop Alzheimer's. Mucke says those failures have prompted scientists to take a closer look at tau. And he says they found some surprising things.

MUCKE: Initially, it was thought that tau was purely inside brain cells, but now we recognize that it can actually exist outside of cells and even transfer from one cell to the next. Researchers have also learned that tau comes in different forms. Julia Gerson from the University of Texas Medical Branch says the most common form of tau actually helps brain cells function.

JULIA GERSON: But in disease for various reasons that we don't entirely understand yet, it takes on this other toxic form.

HAMILTON: A form known as tau oligomers. And this version of tau occurs not only in Alzheimer's patients but also in people with traumatic brain injury. To find out more about toxic tau, Gerson injected tau oligomers from people with Alzheimer's into the brains of healthy mice. Then, her team gave the mice a memory test by replacing one of two familiar objects in their cage with an object they'd never seen before. She says normal mice immediately focus on the new object.

GERSON: But these mice that we've injected with tau oligomers tend to spend the same amount of time looking at both objects. So they don't remember having seen one of them a day before.

HAMILTON: And Gerson who presented her study today at the neuroscience meeting says the team found toxic tau throughout the animal's brains.

GERSON: What we believe is happening is that the toxic form we inject induces the healthy form in the brains of these mice to then take on a toxic confirmation and then to spread through the brain very quickly.

HAMILTON: The idea that tau can spread from cell to cell like an infection is also new. And Lennart Mucke of the Gladstone Institutes says it suggests a way to treat Alzheimer's.

MUCKE: if we could figure out how to stop that spread that would, of course, be very exciting. And maybe one could limit the disease to just some brain regions instead of having it go everywhere.

HAMILTON: Some researchers are already trying to do that using the immune system to mop up toxic forms of tau. A similar strategy has proven effective for reducing amyloid, though it didn't stop Alzheimer's. Mucke says Alzheimer's appears to be a bit like high blood pressure. It can have one more than one cause and may require more than one treatment. He says that means doctors will need a variety of tools.

MUCKE: The problem has been the toolbox was nearly empty. Now what we're seeing is that the toolbox is being filled up with more and more different strategies that one can test and combine.

HAMILTON: And that's giving Alzheimer's researcher a new reason to be optimistic. Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.

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