The How of Tau

The debate over whether the tau protein’s corruption is a cause or effect of the Alzheimer’s disease process is now all but over. In fact, its corruption seems to be a driver of disease not only in Alzheimer’s, but in more than half a dozen other tau-linked maladies.

The Dana Foundation’s latest briefing paper, “The How of Tau,” looks at how tau dysfunction kills and how scientists are working to stop it.

Since the early 1990s, autopsy studies have found that the spread of tau NFTs [neurofibrillary tangles and threads] through memory-related brain areas tracks the progress of Alzheimer’s dementia—and does so better than the spread of Aβ [amyloid beta] plaques. About fifteen years ago scientists also linked a familial form of the dementia syndrome known as frontotemporal dementia with parkinsonism to a set of tau mutations—whose effects turned out to be very similar to what is seen in Alzheimer’s. “Some of the mutations impair the binding of tau to microtubules, while others cause tau to aggregate more readily,” says John Q. Trojanowski, [M.D., Ph.D., a Dana Alliance for Brain Initiatives member who co-directs the Center for Neurodegenerative Disease Research at the University of Pennsylvania.]

Throughout the 2000s, scientists found more and more evidence that tau dysfunction kills and Aβ doesn’t—or rather that Aβ contributes to Alzheimer’s only indirectly, by causing tau dysfunction. The more conclusive findings have come only in the past few years. In 2011, for example, researchers in the Harvard Medical School laboratory of Dennis Selkoe, M.D. (also a Dana Alliance member) reported that small aggregates (“oligomers”) of Aβ, isolated from Alzheimer’s brains, triggered the hyperphosphorylation of tau as well as Alzheimer’s-like changes in neurons, including the loss of synapses, even at very low concentrations. This toxic effect was tau-dependent: no tau, no toxicity.

Read the full paper here.

–Ann L. Whitman

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