Published on: January 13, 2018
by Meredith Wadman for Science:
For the first time, scientists have produced evidence in living humans that the protein tau, which mars the brain in Alzheimer’s disease, spreads from neuron to neuron. Although such movement wasn’t directly observed, the finding may illuminate how neurodegeneration occurs in the devastating illness, and it could provide new ideas for stemming the brain damage that robs so many of memory and cognition.
Tau is one of two proteins—along with β-amyloid—that form unusual clumps in the brains of people with Alzheimer’s disease. Scientists have long debated which is most important to the condition and, thus, the best target for intervention. Tau deposits are found inside neurons, where they are thought to inhibit or kill them, whereas β-amyloid forms plaques outside brain cells.
Researchers at the University of Cambridge in the United Kingdom combined two brain imaging techniques, functional magnetic resonance imaging and positron emission tomography (PET) scanning, in 17 Alzheimer’s patients to map both the buildup of tau and their brains’ functional connectivity—that is, how spatially separated brain regions communicate with each other. Strikingly, they found the largest concentrations of the damaging tau protein in brain regions heavily wired to others, suggesting that tau may spread in a way analogous to influenza during an epidemic, when people with the most social contacts will be at greatest risk of catching the disease.
The research team says this pattern, described in Brain, supports something known as the “transneuronal spread” hypothesis for Alzheimer’s disease, which had previously been demonstrated in mice but not people. “We come down quite strongly in favor of the idea that tau is starting in one place and moving across neurons and synapses to other places,” says clinical neurologist Thomas Cope, one of the study’s authors. “That has never before been shown in humans. That’s very exciting.” Because the researchers looked at Alzheimer’s patients with a range of disease severity, they were also able to demonstrate that, when tau accumulation was higher, brain regions were on the whole less connected. The strength of connections also decreased, and connections were increasingly random.
Nathan Spreng, a neuroscientist who studies brain networks and Alzheimer’s disease at the Montreal Neurological Institute and Hospital in Canada, calls the evidence for an infectionlike spread of tau “fascinating and compelling.” But others note that the study did not follow patients across time, a big weakness that makes it difficult to conclude that “tau spreading” caused the decreased functional connectivity, says Jorge Sepulcre of Harvard Medical School in Boston, who uses PET scanning to probe the impacts of neurodegenerative diseases on brain network connectivity. “The study’s conclusions should be taken cautiously as they do not include longitudinal proof or validation about the spreading nature of tau,” he says.
Yet the global picture of deterioration in the study makes it valuable, Spreng says. “While animal work has looked at how [tau] spread happens from synapse to synapse, this study shows nicely what the brain-wide effects are as the networks start to degenerate in the context of progressive Alzheimer’s disease.” He notes, however, that the small sample size is a concern.
Although he’s confident his team has already demonstrated the transneuronal spread of tau, Cope says that the Cambridge group is now following larger numbers of subjects with Alzheimer’s and tracking individuals across time with brain imaging. The spread of tau could have implications for clinical care, he adds, if drugs can be developed that attack tau in synapses, outside of cells, locking it up inside affected cells early, before it can spread.
Photo: The average accumulation of tau protein, represented by the red spheres, as visualized during positron emission tomography scans of 17 subjects with Alzheimer’s disease.
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