National Institutes of Health/National Institute on Aging (NIH/NIA)
AG027317
United States
National Institutes of Health/National Institute on Aging (NIH/NIA)
AG061775
United States
Citation
Journal: J Struct Biol / Year: 2024 Title: An electrostatic cluster guides Aβ40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy. Authors: Ziao Fu / Elliot J Crooks / Brandon A Irizarry / Xiaoyue Zhu / Saikat Chowdhury / William E Van Nostrand / Steven O Smith / Abstract: Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to ...Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aβ40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aβ40 fibril structures. One population has an ordered N-terminal fold comprised of two β-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.
Entire : Fibrillar assembly of human Amyloid-beta 1-40 derived from vascul...
Entire
Name: Fibrillar assembly of human Amyloid-beta 1-40 derived from vascular deposits in a cerebral amyloid angiopathy patient
Components
Complex: Fibrillar assembly of human Amyloid-beta 1-40 derived from vascular deposits in a cerebral amyloid angiopathy patient
Protein or peptide: Amyloid-beta precursor protein
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Supramolecule #1: Fibrillar assembly of human Amyloid-beta 1-40 derived from vascul...
Supramolecule
Name: Fibrillar assembly of human Amyloid-beta 1-40 derived from vascular deposits in a cerebral amyloid angiopathy patient type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)
Organism: Homo sapiens (human) / Organ: Brain / Tissue: Vasculature
Molecular weight
Theoretical: 4.3299 MDa
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Macromolecule #1: Amyloid-beta precursor protein
Macromolecule
Name: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)
Organism: Homo sapiens (human)
Molecular weight
Theoretical: 4.335852 KDa
Sequence
String:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV
UniProtKB: Amyloid-beta precursor 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: 7.4
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Details
Templated growth from human-derived vascular amyloid deposits
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Electron microscopy
Microscope
FEI TALOS ARCTICA
Image recording
Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Digitization - Frames/image: 1-99 / Number grids imaged: 1 / Number real images: 2075 / Average exposure time: 85.83 sec. / Average electron dose: 49.7 e/Å2
Electron beam
Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
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