Direct visualisation of the beta-sheet structure of synthetic Alzheimer's amyloid.
Amyloid fibrils are a major pathological feature of Alzheimer's disease as well as other amyloidoses including the prion diseases. They are an unusual phenomenon, being made up of different, normally soluble proteins which undergo a profound conformational change and assemble to form very stable, insoluble fibrils which accumulate in the extracellular spaces. In Alzheimer's disease the amyloid fibrils are composed of the A beta protein. Knowledge of the structure of amyloid is essential for understanding the abnormal assembly and deposition of these fibrils and could lead to the rational design of therapeutic agents for their prevention or disaggregation. Here we reveal the core structure of an Alzheimer's amyloid fibril by direct visualisation using cryo-electron microscopy. Synthetic amyloid fibrils composed of A beta residues 11 to 25 and 1 to 42 were examined. The A beta (11-25) fibrils are clearly composed of beta-sheet structure that is observable as striations across the fibres. The beta-strands run perpendicular to the fibre axis and the projections show that the fibres are composed of beta-sheets with the strands in direct register. This observation has implications not only for the further understanding of amyloid, but also for the development of cryo-electron microscopy for direct visualisation of secondary structure.
Serpell
L C
LC
Neurobiology Division, Medical Research Council Centre, Cambridge, UK. serpell@mrc-lmb.cam.ac.uk
Smith
J M
JM
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D020285:Cryoelectron Microscopy; D005583:Fourier Analysis; D007091:Image Processing, Computer-Assisted; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C410220:amyloid beta-protein (11-25)