Determination of the high-resolution structures of tau filaments from the brains of individuals with Alzheimer’s disease (AD) and Pick’s disease (PiD).Methods
Electron cryo-microscopy (cryo-EM) and negative- stain immunogold electron microscopy (immuno-EM) were used.Results
Paired helical filaments (PHFs) and straight filaments (SFs) of AD are made of two identical C-shaped protofilaments that extend from G273/304-E380 (in the numbering of the 441 amino acid isoform of human brain tau). PHFs (the majority species) and SFs (the minority species) are ultrastructural polymorphs, because they differ in their inter-protofilament packing. To date, we performed cryo-EM on four cases and immuno-EM on 19 cases of AD. Narrow Pick filaments (NPFs) and wide Pick filaments (WPFs) are the tau filaments of PiD, a 3R tauopathy. NPFs make up over 90% of filaments. They extend from K254-F378 of 3R tau and are made of a J-shaped protofilament that differs from the AD protofilament. WPFs are formed by the association of two NPF protofilaments. Immuno-EM was used on 9 cases of PiD.Conclusions
There was no significant variation in tau filament structure between individuals with either AD or PiD. However, those structures were very different between AD and PiD, consistent with the existence of molecular conformers of aggregated tau.