The symptoms of neurodegenerative diseases like Alzheimer’s, frontotemporal dementia, and chronic traumatic encephalopathy (CTE) are different, but they have one feature in common: the presence of filaments of misfolded tau protein in patients’ brains. In a new study, scientists at the Medical Research Council Laboratory of Molecular Biology report in unprecedented detail how tau amyloids assemble and become stable (Nature, 2023, DOI: 10.1038/s41586-023-06788-w).
While many diseases feature tau aggregates, in recent years, researchers have found subtle structural differences among filaments associated with those diseases. They have even linked differences in conformation to the speed of disease progression (Sci. Trans. Med. 2022, DOI: 10.1126/scitranslmed.abg0253). Researchers aren’t sure how the diverse filament conformations arise—or for that matter, how any tau filament forms.
In the new study, graduate student Sofia Lövestam and colleagues in Sjors Scheres’ and Michel Goedert’s research groups investigated how a section of the tau protein can aggregate into two types of fibril.
They began with nuclear magnetic resonance spectroscopy to understand the monomer’s floppy structure. While most of the protein moves like cooked spaghetti, Scheres says, some regions are al dente; their rigidity promotes filament formation.
Then the researchers investigated aggregation over time. They used a protocol for filament formation during which tau self-seeds in a simple buffer. A magnesium chloride-containing buffer can yield filaments identical to those from the brains of people with Alzheimer’s. If the buffer contains sodium chloride instead, the filaments resemble those found in the brains of people with CTE. Using cryoelectron microscopy, they determined dozens of different filament structures as each reaction proceeded.
The structures showed something unexpected: The very earliest filament to form appeared in both pathways. That coherence then exploded into a cacophony of differently shaped filaments before both reactions eventually settled into their respective endpoint filaments.
“Amyloid fibrils have historically been proposed to be relatively stable assemblies that do not change over time,” says structural biologist Lukasz Joachimiak of the University of Texas Southwestern Medical Center, who was not involved in the study, in an email. The existence of intermediates was unexpected, and the transitory shared filament even more so—although, Scheres says, “its existence explains a lot of previously reported biochemistry.”
To explain how different filament shapes can arise from the same starting point, the researchers propose a competition between kinetically accessible and thermodynamically stable amyloid forms. The first intermediate may be easy for the protein to reach from its monomeric solution state, but other conformations are more stable to settle into once the protein is in filaments. Which conformation is most stable in the long term depends on the starting chemical environment.
Byron Caughey, a prion expert at the National Institutes of Health, calls the study “an amazing technical feat that really helps us think about how tauopathies . . . get started.” The biggest question it raises, he says, is whether the intermediate tau filaments might be targeted in patients’ brains, or if they are long gone by the time disease develops.
The fibril formation reaction is much simpler than a neuron; the short section of a tau protein comprises only about a quarter of the full-length protein, and the system excludes covalent modifications and noncovalent binding partners that are known to be important in tau aggregation. Because each intermediate is short-lived, it will be difficult to determine whether they really arise in brains in the course of neurodegenerative diseases. Still, knowing these structures could be useful in the design of molecules aimed at “targeting the seed of aggregation, right at the beginning of the seeding process,” says Hélio Albuquerque, a postdoc at the University of Aveiro, who was not involved in the study, in an email.