Cryo-EM structures of τ filaments from human brain

Electron cryo-microscopy (cryo-EM) has made it possible to determine near-atomic structures of tau filaments from human brain. Previous work had shown that the cores of paired helical and straight filaments of Alzheimer's disease are made of two identical, but differently arranged C-shaped protofilaments. In recent years, cryo-EM has shown that the Alzheimer tau fold is 79 amino acids long. Five of the eight beta-strands give rise to two antiparallel beta-sheets, with the other three forming a beta-helix. High-affinity binding sites of positron emission tomography ligand APN-1607 (PM-PBB3) are in the beta-helix region. The Alzheimer fold contrasts with the 94 amino acid-long Pick fold, which is J-shaped and comprises nine beta-strands that give rise to four antiparallel beta-sheets, in the absence of a beta-helix. Chronic traumatic encephalopathy t fold is similar to the Alzheimer fold, but differs in the beta-helix region, which is larger and contains a non-proteinaceous density that is probably hydrophobic. These folds are mostly two-layered. By contrast, the 107 amino acid tau fold of the 4R tauopathy corticobasal degeneration is four-layered and comprises 11 beta-strands. It contains an internal, probably hydrophilic, density that is surrounded by tau. The tau folds described here share the presence of microtubule-binding repeats 3 and 4, as well as 10-13 amino acids after repeat 4.

Automated summary

Electron cryo-microscopy has enabled the determination of near-atomic structures of tau filaments from the human brain. Different types of tau proteins exhibit distinct folding patterns, sharing the presence of microtubule-binding repeats.