3 February 2012. A study reported in the February 1 PLoS One offers an explanation for how tau pathology progresses in Alzheimer’s disease. Researchers led by Karen Duff and Scott Small at Columbia University, New York, made transgenic mice that express human mutant tau predominantly in layer 2 of the entorhinal cortex (ERC), the very region where tau pathology and neuron loss in AD begin. As the animals aged, tau pathology turned up first in the ERC, but then spread to regions of the brain that are innervated by ERC neurons, particularly the hippocampus. “The work leads to the conclusion that misfolded tau moves from one neuron to another, where it acts as a nidus for human and mouse tau to coaggregate,” said Bradley Hyman, Massachusetts General Hospital, Charlestown. Researchers in Hyman’s lab obtained uncannily similar results that are under embargo at the journal Neuron until 23 February, Hyman told ARF. The anatomical spread of tau pathology is akin to that seen upon postmortem examination of human AD brains.
The work made the front page of The New York Times, which suggested that “Alzheimer’s disease seems to spread like an infection from brain cell to brain cell....” Every researcher Alzforum talked with quickly distanced themselves from the notion that AD is infectious. “The term sells newspapers, but it is very misleading,” said Marc Diamond, Washington University, St. Louis, Missouri. “That idea is not supported by these data in any way,” he told Alzforum. Duff agreed. “I would be very, very doubtful that that is a risk,” she said. Hyman said that, as a clinician, he has a much more restricted definition of infectivity. While researchers believe that misfolded, toxic forms of tau can corrupt normal tau molecules in a process called templated protein misfolding, “the notion that there is templated protein alteration is not the same as an infection,” Hyman told ARF. He noted that any protein in the body that forms an oligomer undergoes templated folding. This would include many proteins, such as, for example, hemoglobin. “The fact that this [tau] oligomer is not biologically useful does not make it infectious,” he said.
Hyman said he does not believe The New York Times meant to suggest that someone could catch AD by sitting on a crowded train. Even so, the idea that AD is infectious routinely crops up in lay media headlines as researchers uncover more evidence for propagation of misfolded proteins in the brain. As recently as last October, a scientific report that AD brain extracts induced amyloid plaques when injected into the brains of mice (see ARF related news story) led to press reports asking if Alzheimer’s was infectious or transmissible like bovine spongiform encephalopathy, aka mad cow disease (see, e.g., articles by CBS News, the U.K. Daily Mail, and the Huffington Post). A scientific study led by Mathias Jucker at the University of Tubingen, Germany, reporting that Aβ can spread from the periphery to the brain (see ARF related news story) spurred similar headlines (see io9.com and Cosmos Magazine).
Rumors that Alzheimer’s disease is infectious should be put to rest, said Lary Walker, Emory University, Atlanta, Georgia. Walker was one of the first to investigate transmission of protein pathology in AD. He said he has already been contacted by people from all walks of life in response to The New York Times piece. He called for nuance in reporting the topic, and stressed that Duff’s paper never mentioned infection as a possibility. “Unless there is firm evidence for this, it should not be raised as an issue.” In essence, a pathologic protein spreading from one area of the body to another is a different story from an infectious agent spreading from person to person, researchers agree.
If the new research does not talk about infectivity, what does it say? “It confirms what we have been thinking for quite some time,” said Diamond. Namely, that toxic tau molecules can spread from cell to cell in the brain, and that the route they take tracks Braak staging of the disease, which is based on the progressive appearance of tau pathology in more and more regions of the brain, starting with the entorhinal cortex.
Diamond previously showed that tau, even though it is an intracellular protein, can be passed from one cell to another (see ARF related news story on Frost et al., 2009). “He deserves a lot of credit for starting this type of research in the tau field,” noted Duff. Other amyloidogenic proteins, such as α-synuclein, can spread from cell to cell as well (see ARF related news story). Walker and Jucker found that amyloid-β spreads through the brain if miniscule amounts of aggregated protein are placed there by localized injection (see ARF related news story), and researchers led by Markus Tolnay at the University of Basel, Switzerland, and Michael Goedert at the MRC Laboratory of Molecular Biology, Cambridge, U.K., found that tau spreads in a similar fashion (see ARF related news story).
Duff’s and Hyman’s work show that the same thing can happen in the absence of an injection—by expressing mutant forms of human tau (P301L) in the brain. This has been done before, of course, but what these researchers did differently was to limit expression to layer 2 of the entorhinal cortex.
When the animals reached 10-11 months of age, first author Li Liu and colleagues in Duff’s lab noticed tau aggregates in the ERC. By 22 months, hyperphosphorylated, abnormal tau had spread to the hippocampus, including its subiculum subregion, some pyramidal cells of its CA1 region, and granule cells of the dentate gyrus, which also belongs to the hippocampal formation. The question then became whether the protein in the hippocampus came from the ERC, or if it might have been made in situ due to leaky expression of the tau transgene. Indeed, the peer reviewers of both manuscripts insisted on proof that this was not the reason for the finding, and both labs took steps to eliminate it. Liu used laser capture microscopy to isolate hippocampal cells and amplify their RNA to see if any human tau transcripts were present. They did find some, but felt they were insufficient to explain the amount of human tau protein present. Hyman’s lab took a similar approach, plus also directly compared protein and mRNA in cells of the ERC. As they explained on a poster at the Society for Neuroscience annual meeting last fall (see Polydoro et al., 2011), some ERC cells that tested positive for human tau protein were negative for human tau RNA, suggesting the protein had spread locally from other ERC cells that did express the transgene. “Between both of us, we feel we have tried really hard to rule out artifactual possibilities, leading us to conclude that misfolded human tau is able to move from neuron to neuron,” said Hyman. Duff agreed. “Coupled with Brad’s data, we are very confident that we have the right interpretation,” she told Alzforum.
Questions still remain. How does tau spread from cell to cell? Is tau secreted? Passed through tunneling nanotubes? “All kinds of explanations have been proposed,” said Duff. She plans to study this transfer in vitro and in organotypic tissue culture that preserves the connectivity going from the ERC to the hippocampal formation.
Another major question is whether templated misfolding truly occurs. Diamond said that is still unclear. He suggested that stress on hippocampal neurons resulting from dysfunctional innervation from the ERC could create conditions for local tau aggregation. Jucker raised the same issue in an e-mail to ARF. One sign of templated misfolding would be if the human tau had corrupted the endogenous mouse protein. Hyman said that, in their hands, tau aggregates in the hippocampus comprise both human and mouse tau, indicating that templated misfolding occurs. “If that is the case, then I might be convinced,” wrote Jucker, “but we have to wait to see the paper.”
Do these findings have practical benefit? The anatomical progression of tau pathology in AD—and that of other neurodegenerative proteins, for that matter—has long been a bit of a mystery. Is it due to different vulnerabilities of different brain regions to tau toxicity? Or to spread of toxic tau along routes of anatomic connectivity? This work suggests the latter. “The corollary is that if you could prevent tangles from affecting additional brain areas, you might be able to suppress what we take as a given, which is that the disease progresses,” said Hyman. “Now we have a model system to test that.”—Tom Fagan.
Liu L, Drouet V, Wu JW, Witter MP, Small SC, Clelland C, Duff K. Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012; 7:e31302. Abstract