Biotechnology and Biological Sciences Research Council (BBSRC)
United Kingdom
Citation
Journal: Acta Neuropathol Commun / Year: 2023 Title: Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. Authors: Yang Yang / Alexey G Murzin / Sew Peak-Chew / Catarina Franco / Holly J Garringer / Kathy L Newell / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres / Abstract: We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement ...We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å, revealed differences in the sequence assignment that redefine the fold of Aβ40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aβ proteinopathies.
Entire : Amyloid-beta 40 doublet filament extracted from the human brain w...
Entire
Name: Amyloid-beta 40 doublet filament extracted from the human brain with Alzheimer's disease and cerebral amyloid angiopathy
Components
Tissue: Amyloid-beta 40 doublet filament extracted from the human brain with Alzheimer's disease and cerebral amyloid angiopathy
Protein or peptide: Amyloid-beta A4 protein
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Supramolecule #1: Amyloid-beta 40 doublet filament extracted from the human brain w...
Supramolecule
Name: Amyloid-beta 40 doublet filament extracted from the human brain with Alzheimer's disease and cerebral amyloid angiopathy type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)
Organism: Homo sapiens (human)
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Macromolecule #1: Amyloid-beta A4 protein
Macromolecule
Name: Amyloid-beta A4 protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)
Organism: Homo sapiens (human)
Molecular weight
Theoretical: 4.335852 KDa
Sequence
String:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV
UniProtKB: Amyloid-beta A4 protein
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Experimental details
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Structure determination
Method
cryo EM
Processing
helical reconstruction
Aggregation state
filament
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Sample preparation
Buffer
pH: 7.5
Vitrification
Cryogen name: ETHANE
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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