Alzheimer’s Disease

Scientists have known for years that people who experience traumatic brain injury (TBI) are at greater risk for Alzheimer’s disease later in life. 

Now, new research published in Nature has not only found the mechanism by which TBI causes Alzheimer’s disease, but it has also uncovered a possible cure.

TBI can occur in a variety of ways.

It can come about from large, single impacts, like a blow to the head or from an explosive blast.

It can also accumulate over a lifetime of minor head impacts, such as in contact sports like football or rugby.

Such impacts aren’t rare. In 2010, suspected TBIs sent 2.3 million people to the emergency room.

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Problem Proteins

Previous research has pinpointed misfolded tau proteins as one of the causes of Alzheimer’s disease.

Normally, healthy tau proteins (called trans P-tau) work inside nerve cells to form the scaffolding that gives the cells their shape and allows them to function properly.

Brain Injures

However, when the protein folding process goes awry, the brain can instead form misshapen tau proteins (called cis P-tau).

These proteins malfunction and damage the energy generators inside nerve cells, eventually leading to toxicity and cell death.

Using a brain imaging technique called immunofluorescence, the researchers examined the brains of people with chronic injury-related brain damage. They found that, compared to healthy people, these people had much higher levels of cis P-tau.

The misfolded tau proteins were particularly concentrated in the axons of the nerve cells — the long stalks that nerves project to link up with other cells and form connections.

Mice as Models

To find the causal connection, the researchers turned to mouse models.

Mice that received a single, minor brain injury showed elevated levels of cis P-tau, but these levels dropped back to normal within two weeks.

Mice that received a single, major brain injury (simulating what a soldier surviving an explosion might experience) or a series of minor brain injuries (simulating what an athlete might experience) showed elevated cis P-tau levels that remained for at least six months.

In the severe or chronic brain injury groups, cis P-tau also spread throughout the brain, jumping from one cell to the next and leaving a swathe of cell death in its path. These proteins can spread to the hippocampus and the cortex, which are responsible for memory formation and executive control of emotions and behavior.

Cis P-tau has the ability to kill one neuron after another, eventually leading to widespread neurofibrillary tangles and brain atrophy.
Kun Ping Lu, M.D., Ph.D., Harvard Medical School

“Cis P-tau has the ability to kill one neuron after another, eventually leading to widespread neurofibrillary tangles and brain atrophy, which are the hallmark lesions of both Alzheimer’s disease and [chronic brain injury],” explained Kun Ping Lu, M.D., Ph.D., professor of medicine at Harvard Medical School and chief of the Division of Translational Therapeutics at Beth Israel Deaconess Medical Center, as well as senior co-author on the paper, in an interview with Healthline.

Physical brain injury wasn’t the only thing that could cause cis P-tau to form, either.

The researchers also subjected cultured nerve cells to stress. In particular, starving them of oxygen or brain growth factors, as might happen if blood flow is reduced in the brain after an injury.

The researchers homed in on an enzyme called Pin1, which converts toxic cis P-tau into beneficial trans P-tau. Oxygen starvation deactived Pin1, while lack of growth factor prevented the brain from building new Pin1.

Together, this model of reduced blood flow showed how brain injury and other forms of stress can lead to increased levels of cis P-tau and its toxic effects.

Related Reading: Vision Problems Persist for Veterans Affected by Traumatic Brain Injury »

Antibodies to the Rescue

Once they had identified the problem protein, Lu’s team stepped up to the challenge of how to tackle the issue.

They developed a special antibody that could tag cis P-tau, while leaving trans P-tau alone, and neutralize the toxic protein inside of cells. The antibody could also prevent the cis P-tau from spreading to other cells.

Then came time for the tests. In their stress model, administering the antibodies prevented the cell death that they had seen the cis P-tau cause. 

Next, the researchers tested the antibodies in the mice that had received brain injuries. After two weeks of receiving antibody treatments, mice with brain injuries showed completely normal levels of cis P-tau, and the nerve damage to the axons and energy generators was reversed. The cell death was halted in its tracks.

Finally, Lu’s team tested the behavior of the mice. Healthy mice showed caution in a risk-taking task that is typical of mice. Mice with brain injuries that had been given a sham antibody as a placebo, however, showed striking risk-taking behavior, much like many humans who have survived brain injury.

But brain injured mice who were given the special antibody that targets cis P-tau didn’t show this risky behavior. Instead, they were as cautious as the healthy mice.

“Our subsequent and ongoing experiments show that pre-treatment and [brain] injection are not necessary,” said Lu. “We can delay antibody treatment [hours] after TBI and give three to four antibody injections, which is effective. These results suggest that a short-term antibody treatment after TBI might be sufficient for treating TBI and preventing its long-term consequences if there is not further brain injury.”

Can It Prevent Alzheimer’s?

As for whether this treatment can also prevent the development of Alzheimer’s disease, Lu is working on the problem.

Since Alzheimer’s disease is age-dependent, he must wait for his test mice to grow older before he will see results. But the theory is promising.

There are some limitations to his team’s findings. Mouse models, especially of Alzheimer’s disease, don’t perfectly duplicate the human version of the disease. And it will take time to develop a version of the antibody that works in humans.

But Lu is optimistic.

“Antibody technology is a popular drug development approach due to its extraordinary specificity and high success rate,” he said. “Moreover, the process to convert our current mouse antibody to one that can be tested in humans has been streamlined and can be done within a couple of years. Obviously, this will depend on funding.”

He added, “These findings uncover a novel, common early disease mechanism in sport- and military-related TBI and Alzheimer’s disease, and may lead to early diagnosis, prevention, and therapy of these devastating diseases.”

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