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Strains of Misfolded Tau Transmitted in Mice, Found in Human Brain

Robinson, Richard

doi: 10.1097/01.NT.0000453251.92259.a0
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Investigators reported that strains of tau could be misfolded in different ways into different strains that were linked in postmortem tissue to Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, and other tauopathies.

Misfolded tau forms distinct strains that can be serially propagated both in vitro and in vivo, according to a study in the June 18 issue of Neuron. That faithful cell-to-cell transmission of misfolded tau brings tauopathies under the umbrella of prion diseases, according to lead author Marc Diamond, MD, a professor of neurology at the Washington University in Saint Louis School of Medicine in Missouri.

Furthermore, he said, different human tauopathies are characterized by different constellations of strains, suggesting that multiple anti-misfolding therapies may be required to successfully treat Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, and other tauopathies.

The prion concept began with the recognition that certain proteins could act as templates to cause molecules of the same protein to fold into the same conformation, which could go on to template the folding of yet more protein. The first such proteins identified, called prion proteins (PrP), caused neurodegenerative diseases of humans and ungulates (including sheep and cows), and were transmissible to some extent within species, and to a much lesser extent between species.

Since then, the concept has been extended to include many of the proteins associated with neurodegenerative diseases, including amyloid-beta in Alzheimer's disease, alpha-synuclein in Parkinson's disease, and tau in the tauopathies. While there is little evidence to date suggesting that these proteins are spread between organisms, the strong similarities in templating and spreading between cells has led many in the field to use the term “prion” to describe them as well.

“From a cell biology standpoint, it is exactly like a prion,” Dr. Diamond said.

A characteristic of PrP is the existence of strains, unique conformations that are passed on in the templating process. Strains differ in several clinically important aspects, including the incubation period, Dr. Diamond said. Classic Creutzfeldt-Jakob disease (CJD) and new variant CJD (the human version of “mad cow disease”) are due to different strains.

Tau is a microtubule-associated protein that in its normal state is soluble. Both mutations and hyperphosphorylation can decrease its solubility, leading to formation of amyloid and protein aggregates, which are found in multiple neurodegenerative diseases.

While templating and cell-to-cell transmission have been previously shown for tau, faithful maintenance of strains has not, Dr. Diamond said. That led him to determine whether tau shared this characteristic with the PrPs. This is important, he said, because to the extent that prion mechanisms underlie the tauopathies, “only stably propagating strains can account for stereotyped clinical presentation” and spread through networks of brain neurons.

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To test for the presence of strains in tau, Dr. Diamond used the aggregation-prone core of the protein, the repeat domain, bearing an aggregation-prone mutation, to transduce cells in culture. After several days, individual aggregate-containing cells were isolated and grown up separately. At the end of a month, Dr. Diamond analyzed the progeny cells to determine whether they contained identifiably different strains.

Based on aggregate morphology, he identified 20 different clones. One, called clone 9, featured small juxtanuclear tau inclusions with many nuclear speckles, while another, clone 10, contained a single large juxtanuclear inclusion. Clone 9 led to quick formation of inclusions in naïve cells, but the inclusions grew slowly, while clone 10 seeded other cells slowly, but the inclusions themselves grew quickly.

Each clone maintained its inclusion type over the course of six months of cell culture, and thus, Dr. Diamond concluded, were true strains of tau aggregates.

Different strains induced different pathologies in mice expressing a mutant tau protein, and after two rounds of isolation and reinjection into naïve mice, the same strain as originally injected could be isolated again from the mouse brain. Within the brain, the tau aggregates spread from the site of injection to distant, synaptically connected regions.

“Tau is acting like an infectious agent according to Koch's postulates, from the standpoint of cell biology,” Dr. Diamond said.

Finally, Dr. Diamond searched for tau strains in the brains of 29 patients with tauopathies, including Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, and others. He isolated tau aggregates from each brain, and used them to induce inclusions in cell culture, and then classified the inclusions based on morphology, similar to the earlier identification of the 20 clones.



Four of the six AD brains induced a single type of inclusion; the two remaining AD brains induced predominantly that same type, and small amounts of a second type. Several patients with corticobasal degeneration contained the same two strains as the mixed-type AD patients, but in opposite proportions. Other diseases were more heterogeneous, with multiple types of inclusions both within a single patient and between patients with the same diagnosis. Two patients with progressive supranuclear palsy had all of one strain, and two others had all of a second strain, while two additional patients had none of either of those strains, but bore different mixes of three other strains.

“As with prion diseases,” Dr. Diamond explained, “individuals are harboring a kind of ‘cloud’ of different conformers all at once, and the disease is probably the integration of the effects of each of these conformers. Because we demonstrate the strains are stable, it suggests that in theory we should be able to define human diseases based on the strain compositions of their tau aggregates.”

“Currently we classify these diseases based on their clinical presentation, and then the neuropathology. What we are saying is, there is a nuance to the diseases that is as yet unappreciated, because we have not looked at the molecular structure of the causal agent.”

The analogy, he said, was to cancer of, say, the colon, which clinically may look like one disease, but is actually multiple diseases due to disordered signaling of different genes, which will be responsive to different drugs.

“We are moving toward understanding these diverse neurodegenerative diseases based on the structure of the pathogenic forms of the protein,” he said. “By the time we are done, I hope we will be able to diagnose diseases based on molecular structure, and use that to make predictions of clinical course and potentially even response to therapy.”

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Kurt Giles, DPhil, an associate professor of neurology at the University of California, San Francisco, commented to Neurology Today that this work and similar discoveries “mark the start of a new field,” based on the recognition that most, if not all, neurodegenerative diseases are prion-like. “Aggregation, templating, and spreading really seems to be common to them all.”

“This study is an elegant demonstration of tau strains,” and adds to the growing recognition of strains of disease proteins in a variety of neurodegenerative diseases, according to John Trojanowski, MD, PhD, a professor of pathology and laboratory medicine, co-director of the Center for Neurodegenerative Disease Research, and co-director of the Marian S. Ware Alzheimer Drug Discovery Program at the University of Pennsylvania in Philadelphia. However, Dr. Trojanowski said, the term “prion” is misused in this context, since prions were specifically described as infectious, based on their ability to spread between organisms, not simply from cell to cell.

Dr. Giles is comfortable with the term, however. More significantly, he said, the transmission of strains within the brain “has therapeutic implications,” including the idea that different strains may require different therapies, tailored to the conformation and replication properties of each. And a treatment that preferentially eliminated one strain might lead to a surge in the population of a second, more resistant one. “It is a daunting challenge, but it is something we need to pay attention to.”

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•. Sanders DW, Kaufman SK, DeVos SL, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 2014;82(6):1271–1288.
    •. Neurology Today archive on prions and neurodegenerative disease:
      © 2014 American Academy of Neurology