Toxic Tau Could be Key to Alzheimer’s Treatment

For years, Alzheimer’s researchers have targeted amyloid beta in attempts to halt the progression of the disease, without success. Now, they have their sights set on a second brain protein: tau. And the findings are promising.

Tau is responsible for the tangles that form in the brains of people with Alzheimer’s, while the protein amyloid beta causes the sticky plaques associated with the disease. Although the focus has shifted to tau, “Amyloid beta is still a player,” said Tong Li, Ph.D. of The Johns Hopkins University in Baltimore, MD. “Amyloid plaques speed up the formation and spread of the tau aggregates, which leads to neuronal loss.”

“But now, we know that tau is not simply a bystander but also a player,” Li said. “Both proteins work together to damage cell functions as the disease unfolds.”

Targeting tau

In the healthy brain, tau protein helps with the building and functioning of neurons. But when tau malfunctions, it creates abnormal clumps of protein fibers—neurofibrillary tangles—which spread rapidly throughout the brain. This highly toxic and altered form of the brain protein tau is called “tau oligomer.”

“There’s growing evidence that tau oligomers, not tau protein in general, are responsible for the development of neurodegenerative diseases, like Alzheimer’s,” said Julia Gerson, a graduate student in neuroscience at the University of Texas Medical Branch.

In Gerson’s research, which she presented at this year’s Society for Neuroscience meeting in Washington, D.C., Gerson and her team injected tau oligomers from people with Alzheimer’s into the brains of healthy mice. Subsequent testing revealed that the mice had developed memory loss.

“When we inject mice with tau oligomers, we see that they spend the same amount of time exploring a familiar object as an unfamiliar object,” said Gerson. “So they’re incapable of remembering that they’ve already seen this familiar object.”

What’s more, the molecules had multiplied throughout the animals’ brains. “This suggests that tau oligomers may spread from the injection site to other unaffected regions,” said Gerson.

Future treatments

Understanding tau’s connection to Alzheimer’s could have implications for potential therapies. “If we can stop the spread of these toxic tau symptoms,” said Gerson. Gerson’s lab is currently investigating antibodies, which specifically fight tau oligomers.

Erik Roberson, M.D., Ph.D., at the University of Alabama at Birmingham, and colleagues looked at how boosting the function of a specific type of neurotransmitter receptor, the NMDA receptor, provided benefit to people with the second most common type of dementia: frontotemporal dementia (FTD), a disease in which people experience rapid and dramatic changes in behavior, personality and social skills. People often quickly deteriorate and usually die about three years after diagnosis; there is also no effective treatment for FTD.

Since mutated tau impairs synapses—the connections between neurons—by reducing the size of NMDA receptors, “boosting the function of remaining NMDA receptors may help restore synaptic firing, and reverse behavioral abnormalities,” said Roberson.
Roberson’s, along with others’ work presented at the Society of Neuroscience meeting, focused on using animal models that mimic developing tau pathology. “These new mouse models, which contain both tau tangles and amyloid plaques” said Dr. Li, “offer the possibility of more accurately testing therapies directed at delaying the onset of amyloid beta plaques, tau accumulation and neuronal loss, all characteristic features of Alzheimer’s.”

Are clinical trials next?

Potentially, yes. “This arena of academic research has been ongoing for several years—it’s a younger area in terms of involvement of drug discovery,” said Sangram Sisodia, Ph.D., director of the Center for Molecular Neurobiology at the University of Chicago. “But I believe there is growing interest in pharma companies about targeting tau.

“The tau protein plays an incredibly complex role in the development of Alzheimer’s and other neurodegenerative diseases,” said Sisodia. “We are in the early stages of understanding that role, which will be crucial for developing effective preventions or treatments.”

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