No abstract

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances ( 1 – 3 ). A higher frequency of the H1 haplotype of MAPT , the tau gene, is present in cases of CBD than in controls ( 4 , 5 ) and genome-wide association studies have identified additional risk factors ( 6 ). By histology, astrocytic plaques are diagnostic of CBD ( 7 , 8 ), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE ( 9 ). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) ( 10 ), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) ( 11 – 15 ). This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments ( 16 ). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE ( 17 – 19 ). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.

These data support distinct processes in the initiation and progression of AD pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al . used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SMH