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PLAQUE BUILDUP IN THE BRAIN:
Leads to dementia // In Alzheimer's, amyloid-beta protein gets the blame // But is tau the true culprit?

Tangled Up in Tau

By Anita Slomski // Illustrations by Harry Campbell
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Yarn in tangles inside an illustrated human head

Harry Campbell

Neurologist Bruce Miller calls tau—a floppy, free-form protein—“the holy grail of dementia.” That designation may come as a surprise to anyone who has even a passing interest in the science of end-of-life brain diseases. A different protein, amyloid-beta (Aß), has become famous as the culprit responsible for the so-called senile plaques that gum up the brains of people with Alzheimer’s disease. Yet tau also plays a role in Alzheimer’s, by far the most prevalent type of dementia, and it’s not Aß but tau, escaping its proper place inside neurons, that attacks the brain in a host of similar diseases.

According to Miller, who heads the Memory and Aging Center at the University of California, San Francisco, and the Tau Consortium, an international research program, knowledge of Aß emerged before much was known about tau. As a result, pharmaceutical companies have invested considerable sums developing therapies that target Aß. Yet so far, all trials attempting to clear Aß plaques from the brain have failed to slow down the disease or to produce any cognitive improvement in people with early stages of Alzheimer’s disease.

As discoveries about tau were made, however, it became increasingly clear that the protein may be a major contributor to many kinds of dementia, which could be more closely related to one another than anyone had guessed. “We’ve gone from thinking of tau as not very interesting to understanding that tau pathology leads to multiple diseases that have different clinical symptoms based on which brain region and type of neurons are affected,” says Michel Goedert, head of the neurobiology division at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. In 1996, he and Bernardino Ghetti of Indiana University coined the term tauopathy to describe diseases that have tau inclusions as their common, defining denominator.

Among the more than two dozen tauopathies is frontotemporal dementia (FTD), which leads to impaired social skills, language loss and personality changes. Another, corticobasal degeneration, causes the rigidity and abnormal postures of Parkinson’s disease as well as difficulty with speech and swallowing and the perception that an arm or a leg isn’t part of your own body. There’s also progressive supranuclear palsy, characterized by balance and eye problems, depression, apathy and dementia. Still another tauopathy—chronic traumatic encephalopathy—may arise in football players, war veterans and others who have suffered repeated concussions or other brain trauma.

The latest revelation about tau, in late 2012, helps explain why diseases of dementia progress slowly, with tau tangles destroying millions of neurons in a chain reaction that progresses from one region of the brain to the next. “That understanding gives us a whole panoply of new therapeutic targets,” says Bradley Hyman, director of the Memory Disorders Unit at Massachusetts General Hospital and one of the researchers who discovered how tau pathology spreads. It appears to be possible, for example, to use antibodies for clearing the neurofibrillary tangles or to come up with a way to block nerve cells from taking up the tangles and destroying themselves.

The possibility of eliminating abnormal tau offers hope for solving the riddles of several types of dementia. “I think we may find a cure for frontotemporal dementia before Alz-heimer’s disease because we have a pure target in tau,” says Miller. The ability to go after tau problems in those diseases, by itself, could have an enormous impact. And while researchers are still in the early days of determining how tau interacts with Aß in Alzheimer’s disease and deciding which protein is the more toxic at different stages of the disease, knowing how to get rid of tau tangles might also be one key to developing an effective therapy for Alzheimer’s disease.

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An Avoidable Dementia

One tauopathy is entirely man-made, caused by concussions and other types of brain trauma.

From One Protein, Many Diseases

Depending on where tau tangles form in the brain, any of a number of types of dementia may occur.

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hed-dossier

1. “Tau Pathology and Neurodegeneration,” by Maria Grazia Spillantini and Michel Goedert, The Lancet Neurology, June 2013. A comprehensive overview of the most recent research on the genetics of tau dysfunction, the role of tau in dementias, the way tau is thought to spread in the brain, and the interaction of amyloid-beta and tau in Alzheimer’s disease.

2. “Developing Therapeutic Approaches to Tau, Selected Kinases and Related Neuronal Protein Targets,” by Virginia M-Y Lee et al., Cold Spring Harbor Perspectives in Medicine, 2011. The authors speculate that ridding the brain of tau tangles—which occur when memory deficits start—may be more effective than purging the amyloid-beta plaques of Alzheimer’s disease, which form many years before symptoms do.

3. “Artistic Creativity and Dementia,” by Zachary A. Miller and Bruce L. Miller, Progress in Brain Research, Volume 204, 2013. A fascinating account of a subset of patients with frontotemporal dementia who develop new creativity in the visual or verbal arts.

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