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Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold

By Benjamin Falcon, Wenjuan Zhang, Manuel Schweighauser, Alexey G. Murzin, Ruben Vidal, Holly J. Garringer, Bernardino Ghetti, Sjors Scheres, Michel Goedert

Posted 07 Sep 2018
bioRxiv DOI: 10.1101/411215 (published DOI: 10.1007/s00401-018-1914-z)

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of typical AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of typical AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for a case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament structure. The immuno-EM findings, which established the presence of repeats 3 and 4, but not repeats 1 and 2, of tau in the filament cores of all AD cases and brain regions thereof, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies.

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