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Tangled Up in Tau

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A hand holding a tangled ball of yarn

Harry Campbell

Tau was identified in 1974 by cell biologist Marc Kirschner as one of several proteins that form a nerve cell’s microtubules (MTs), structures that are part of a neuron’s axon—a long projection that extends from the cell body to the synapses, the connections through which nerve impulses are transmitted from one neuron to the next. MTs transport nutrients and other substances into and out of the cell body, and tau’s role is to stabilize those vital structures. “Think of microtubules as the train tracks that carry cargo to the cells, with tau being the crossties that support them,” says neuropathologist John Trojanowski. He and his wife, biochemist Virginia Lee, are among the pioneers studying tau and head the Center for Neurodegenerative Disease Research and Center for Alzheimer’s Drug Discovery Program at the University of Pennsylvania’s Perelman School of Medicine.

Material produced in neurons gets shipped via MTs to the synapses, which enables the synapses to release neurotransmitters that carry signals to other neurons. “The neuron has engineered a just-in-time delivery mechanism to supply nerve terminals with everything they need to function, so they’ll be instantly ready if you have to quickly command your limbs to jump out of the way of a car, for example,” says Trojanowski. And that cargo may have to travel a long way. Motor neurons, for example, have axons that stretch from the top of the head to the lower back. Strong, intact MTs are crucial if nerve cells are to communicate with one another.

By the late 1980s, scientists had identified tau as the protein forming the filaments that clump together within neurons to form tangles that, along with Aß plaques, are pathological hallmarks of Alzheimer’s disease. A breakthrough came in 1998, when researchers found mutations on the tau gene that cause FTD. There are now more than 50 known mutations of the tau gene, which either impair the way tau binds to MTs or promote the aggregation of tau into filaments. Additional “susceptibility” genes are just starting to be sorted out, Miller says.

Fewer than one in 10 tauopathies can be traced to tau gene mutations. Nevertheless, the discovery that mutations on the tau gene cause FTD “put tau on equal footing with Aß and meant it should no longer be considered an incidental or secondary disease process,” says Dennis Dickson, professor of Alzheimer’s disease research at the Mayo Clinic in Florida. What it did not do, however, was end conflicts between so-called BAPtists—researchers who maintained that Aß (also called beta-amyloid protein, or BAP) was the primary cause of Alzheimer’s—and the growing ranks of Tauists. “There were vituperative clashes about which protein was most important in Alzheimer’s disease,” says Trojanowski.

The BAPtists claimed that Aß plaques form in the brain first and lead to problems with tau—and that getting rid of Aß was a prerequisite for halting the progress of Alzheimer’s. For their part, the Tauists pointed out that a third of elderly people without dementia have brains with numerous Aß plaques when they die—and that therefore it must be tau, not Aß, that is behind the neurodegeneration of Alzheimer’s.

But then came the failure of trial after trial of therapies designed to clear Aß from the brains of people with mild cognitive impairment. Even approaches that succeeded in reducing the plaques did nothing to reduce Alzheimer’s symptoms, and Hyman believes that a combination of treatments is likely to be needed, as has been the case in other diseases. “Lower cholesterol plays a big role in preventing heart attacks, but so does controlling blood pressure,” he says. “And to treat most cancers, you need a cocktail of chemotherapeutic agents. So it wouldn’t be surprising if we need agents to tackle both Aß and tau as well as maybe inflammation and other factors,” he adds.

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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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