Misfolded proteins that cause neurodegenerative diseases act an awful lot like prions, even if they do not fit the exact definition. For example, Aβ and tau are not considered infectious from person to person, and no one has shown that distinct conformations stably pass between animals while keeping their shape as prions do. That is, until now. In the May 22 Neuron online, scientists led by Marc Diamond, Washington University in St. Louis, report that misfolded forms, or “strains,” of tau can propagate from one mouse to the next by injection, suggesting the protein behaves more like a prion than previously realized. “This is a carefully done and exciting study that convincingly demonstrates the existence of tau strains in living systems,” Mathias Jucker, University of Tübingen, Germany, wrote in an email to Alzforum (see full comment below).
Tau can misfold in many different ways. At last year’s Alzheimer’s Association International Conference, held in Boston, Diamond revealed that different conformations, or strains, of the protein manifest unique physical properties and toxicities (see Aug 2013 news story). When inoculated into successive cultures of naïve cells, each strain seeded its own particular brand of inclusion over and over. Other researchers wondered whether this faithful tau transmission would occur in a more natural system.
To demonstrate this, co-first authors David Sanders and Sarah Kaufman and colleagues made tau fibrils in vitro and used them to corrupt a tau fragment expressed in HEK293 cells. These cells expressed the core, aggregation-prone portion of tau, called the repeat domain (tau RD). Sanders isolated single colonies and picked two to characterize more fully—clone 9 and clone 10. Clone 10 produced larger aggregates that lay outside the nucleus. Clone 9 seeded more efficiently and produced many small intranuclear deposits.
The researchers then injected these two strains into transgenic mice expressing full-length human mutant tau (P301S), which causes inherited tauopathies. After three weeks, they looked at pathology in the brain. Clone 9 caused tangle-like aggregates in the CA1 and CA3 areas of the hippocampus, while clone 10 led to puncta in the mossy fiber tracts of CA3. When Sanders and colleagues injected brain homogenates from these animals into a second group of mice, and four weeks later transferred brain material from those to a third group, each new recipient developed similar clone-specific pathology. When they extracted the tau from the third round of mice and put it back into tau RD-expressing HEK293 cells, inclusions formed that were identical to those in the initial tau RD cells.
How does the stable passage of a specific strain of misfolded tau relate to human disease? As Diamond presented at AAIC, different human tauopathies seem to come with their own unique tau conformations. Cell cultures seeded with brain extracts from 29 patients revealed that Alzheimer’s disease tissue induces patterns of tau inclusions that almost exclusively appeared speckled, while those generated by corticobasal degeneration extracts were mostly disordered, and Pick’s tissue yielded mosaics (see image). These results echoed a recent study showing patient brain extracts seeded disease-specific tau pathology in mice (see Clavaguera et al., 2013). “We think the molecular structure of the aggregate will allow us to predict the disease it came from,” said Diamond.
Up to now, only bona fide prions have shown the ability to stably hold their shape between inoculations from one animal to the next, Diamond said. His data support the idea that tau should be considered a prion, he argues. Lary Walker, Emory University, Atlanta, told Alzforum that this new study strongly supports the prion concept in neurodegenerative disease pathogenesis. Uniting the neurodegenerative and prion fields would be helpful because people who study neurodegeneration could learn from the extensive literature already available for prions, he said.
However, Walker and several other scientists noted that in the public imagination, the word “prion” connotes infectivity. Spreading the erroneous idea that tauopathies are contagious in the way of prion diseases such as bovine spongiform encephalopathy could cause unnecessary anxiety. “As a field, we have to agree on a less frightening definition of prion, or come up with another word that encapsulates all of these diseases,” Walker said (see additional email comment below).
Diamond said that while spontaneous transmission does not occur between people, under the right circumstances—tissue transplantation, for instance—pathogenic proteins such as tau could conceivably be passed among individuals. The field should be aware of that possibility, he said. A survey counters that idea, reporting that when people received human growth hormone prepared from the pooled pituitary glands of cadavers that likely contained traces of Aβ, tau, or α-synuclein, the incidence of AD and PD did not rise (see Feb 2013 news story). In the future, Diamond and colleagues plan to examine patients with tauopathies to see if their diseases can be defined by aggregate structures and tau conformations. They will also examine whether tau strains dictate how pathology spreads, and look for genes that promote it, with an eye toward new drug targets.
Walker pointed out that the study has implications for therapeutics. It suggests that a molecule could bind and disrupt tau aggregation in mice but prove ineffective in humans because of the differences in tau’s conformation. “That means you may want to be as close as possible to the ultimate target when developing a drug,” he told Alzforum. On the plus side, Luc Buée of INSERM in Lille, France, added that researchers may be able to tailor therapies to target specific conformations of tau and avoid the normal protein.
In related news, Walker and Jucker on May 15 won, along with one other scientist, the 2014 MetLife Foundation Award in Medical Research for their pioneering work on the prion-like nature of Aβ, on which Diamond based his current research (see May 2014 news story).
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