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- EMDB-50436: Cryo-EM Structure of Amyloid-beta Fibrils from Mouse Brain Carryi... -

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Entry
Database: EMDB / ID: EMD-50436
TitleCryo-EM Structure of Amyloid-beta Fibrils from Mouse Brain Carrying the Uppsala AbetaUpp(1-42)delta(19-24) Mutation
Map datamain map, masked, symmetry applied.
Sample
  • Tissue: Amyloid fibrils of amyloid-beta(1-42)delta(19-24) extracted from mouse brain.
    • Protein or peptide: Amyloid-beta precursor protein
KeywordsAmyloid Fibril / PROTEIN FIBRIL
Function / homology
Function and homology information


collateral sprouting in absence of injury / axo-dendritic transport / regulation of synapse structure or activity / axon midline choice point recognition / mating behavior / Golgi-associated vesicle / neuron remodeling / dendrite development / signaling receptor activator activity / transition metal ion binding ...collateral sprouting in absence of injury / axo-dendritic transport / regulation of synapse structure or activity / axon midline choice point recognition / mating behavior / Golgi-associated vesicle / neuron remodeling / dendrite development / signaling receptor activator activity / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / Notch signaling pathway / clathrin-coated pit / extracellular matrix organization / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / axonogenesis / central nervous system development / adult locomotory behavior / locomotory behavior / serine-type endopeptidase inhibitor activity / recycling endosome / visual learning / cognition / endocytosis / neuron projection development / heparin binding / regulation of translation / growth cone / perikaryon / early endosome / cell adhesion / membrane raft / signaling receptor binding / axon / apoptotic process / cell surface / endoplasmic reticulum / Golgi apparatus / DNA binding / extracellular region / nucleus / membrane / plasma membrane / cytoplasm
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodhelical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZielinski M / Peralta Reyes FS / Gremer L / Pagnon de la Vega M / Roeder C / Heidler TV / Syvaenen S / Willbold D / Sehlin D / Ingelsson M / Schroeder GF
Funding support Germany, 1 items
OrganizationGrant numberCountry
Helmholtz AssociationIVF Germany
CitationJournal: Acta Neuropathol Commun / Year: 2025
Title: Cryo-EM studies of amyloid-β fibrils from human and murine brains carrying the Uppsala APP mutation (Δ690-695).
Authors: Mara Zielinski / Fernanda S Peralta Reyes / Lothar Gremer / Simon Sommerhage / María Pagnon de la Vega / Christine Röder / Thomas V Heidler / Stina Syvänen / Dieter Willbold / Dag Sehlin ...Authors: Mara Zielinski / Fernanda S Peralta Reyes / Lothar Gremer / Simon Sommerhage / María Pagnon de la Vega / Christine Röder / Thomas V Heidler / Stina Syvänen / Dieter Willbold / Dag Sehlin / Martin Ingelsson / Gunnar F Schröder /
Abstract: Today, 13 intra-amyloid-β (Aβ) amyloid precursor protein (APP) gene mutations are known to cause familial Alzheimer's disease (AD). Most of them are point mutations causing an increased production ...Today, 13 intra-amyloid-β (Aβ) amyloid precursor protein (APP) gene mutations are known to cause familial Alzheimer's disease (AD). Most of them are point mutations causing an increased production or a change in the conformation of Aβ. The Uppsala APP mutation (Δ690-695 in APP, Δ19-24 in Aβ) is the first known multi-codon deletion causing autosomal dominant AD. Here, we applied cryo-electron microscopy (cryo-EM) to investigate the structure of Aβ fibrils with the Uppsala APP mutation from tg-UppSwe mouse brain tissue. Murine AβUpp(1-42) are made of two identical S-shaped protofilaments with an ordered fibril core of S8-A42. The murine Aβ fold is almost identical to previously described human type II filaments, although the amino acid sequences differ considerably. In addition, we report the cryo-EM structure of Aβ fibrils from the temporal cortex of a patient with the Uppsala APP mutation. The observed structure of the human Aβ fold closely resembles previously described type I fibrils. Structural modeling suggests that these fibrils are composed of wild-type Aβ, which implies that AβUpp may be less soluble and thus not readily accessible for cryo-EM image processing and structure determination. Additionally, from the human sample we determined the structures of tau paired helical filaments and tau straight filaments, which are identical to those found in sporadic AD cases. Finally, we present the 3D cryo-EM structures of four dominant AβUpp(1-42) fibril polymorphs, formed in vitro. All four polymorphs differ from the observed folds of Uppsala Aβ in murine and human brain tissue, respectively.
History
DepositionMay 26, 2024-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateOct 22, 2025-
Current statusOct 22, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50436.png

Downloads & links

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Map

FileDownload / File: emd_50436.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map, masked, symmetry applied.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 300 pix.
= 242.4 Å		0.81 Å/pix.
x 300 pix.
= 242.4 Å		0.81 Å/pix.
x 300 pix.
= 242.4 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.808 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.029
Minimum - Maximum-0.13328013 - 0.2149604
Average (Standard dev.)0.0005931167 (±0.009811268)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 242.40001 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map 1

Fileemd_50436_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_50436_half_map_2.map
Annotationhalf map 2
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid fibrils of amyloid-beta(1-42)delta(19-24) extracted from ...

EntireName: Amyloid fibrils of amyloid-beta(1-42)delta(19-24) extracted from mouse brain.
Components
  • Tissue: Amyloid fibrils of amyloid-beta(1-42)delta(19-24) extracted from mouse brain.
    • Protein or peptide: Amyloid-beta precursor protein

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Supramolecule #1: Amyloid fibrils of amyloid-beta(1-42)delta(19-24) extracted from ...

SupramoleculeName: Amyloid fibrils of amyloid-beta(1-42)delta(19-24) extracted from mouse brain.
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse) / Organ: brain / Tissue: brain

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Macromolecule #1: Amyloid-beta precursor protein

MacromoleculeName: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse) / Organ: brain / Tissue: brain
Molecular weightTheoretical: 3.81133 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVGS NKGAIIGLMV GGVVIA

UniProtKB: Amyloid-beta precursor protein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.36 Å
Applied symmetry - Helical parameters - Δ&Phi: 178.4 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 329437
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: a featureless cylinder with diameter of 140 Ang.
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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