EMDB-50440: Cryo-EM Structure of Amyloid-beta Fibrils Carrying the Uppsala Ab...

Basic information

Entry

Database: EMDB / ID: EMD-50440

• Title: Cryo-EM Structure of Amyloid-beta Fibrils Carrying the Uppsala AbetaUpp(1-42)delta(19-24) Mutation - Polymorph 4
• Map data: primary map

Sample

• Tissue: Amyloid fibrils of amyloid-beta(1-42)delta(19-24)
  • Protein or peptide: Amyloid-beta precursor protein

• Keywords: Amyloid Fibril / PROTEIN FIBRIL

Function / homology

Function:

amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / hippocampal neuron apoptotic process / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / axo-dendritic transport / axon midline choice point recognition / regulation of synapse structure or activity / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / Golgi-associated vesicle / PTB domain binding / astrocyte projection / Lysosome Vesicle Biogenesis / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / neuron remodeling / nuclear envelope lumen / dendrite development / regulation of multicellular organism growth / TRAF6 mediated NF-kB activation / positive regulation of protein metabolic process / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / transition metal ion binding / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / modulation of excitatory postsynaptic potential / main axon / intracellular copper ion homeostasis / ECM proteoglycans / Notch signaling pathway / response to insulin-like growth factor stimulus / positive regulation of T cell migration / regulation of presynapse assembly / neuronal dense core vesicle / swimming behavior / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / adult locomotory behavior / positive regulation of mitotic cell cycle / axonogenesis / extracellular matrix organization / cellular response to manganese ion / positive regulation of chemokine production / neuron projection maintenance / clathrin-coated pit / astrocyte activation / Mitochondrial protein degradation / regulation of neuron apoptotic process / ionotropic glutamate receptor signaling pathway / platelet alpha granule lumen / learning / response to interleukin-1 / cellular response to copper ion / positive regulation of glycolytic process / cellular response to cAMP / endosome lumen / trans-Golgi network membrane / positive regulation of interleukin-1 beta production / dendritic shaft / positive regulation of long-term synaptic potentiation / protein serine/threonine kinase binding / locomotory behavior / central nervous system development / Post-translational protein phosphorylation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / microglial cell activation / cellular response to nerve growth factor stimulus / visual learning / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / synapse organization / positive regulation of interleukin-6 production / recycling endosome / response to lead ion / Golgi lumen / positive regulation of JNK cascade / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / neuron projection development / endocytosis / positive regulation of inflammatory response / calcium ion transport / positive regulation of tumor necrosis factor production / Platelet degranulation / heparin binding / regulation of translation / regulation of gene expression

Domain/homology:

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, heparin-binding / Amyloid A4 N-terminal heparin-binding / 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, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / 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

Component:

Amyloid-beta precursor protein

• Biological species: unidentified (others) / Homo sapiens (human)
• Method: helical reconstruction / cryo EM / Resolution: 3.8 Å
• Authors: Zielinski 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

Organization	Grant number	Country
Helmholtz Association	IVF	Germany

• Citation: Journal: 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 / 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 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

Deposition	May 26, 2024	-
Header (metadata) release	Jun 11, 2025	-
Map release	Jun 11, 2025	-
Update	Oct 22, 2025	-
Current status	Oct 22, 2025	Processing site: PDBe / Status: Released

Map

• File: Download / File: emd_50440.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• Annotation: primary map
• Voxel size: X=Y=Z: 0.816 Å

Density

Contour Level	By AUTHOR: 6.91
Minimum - Maximum	-11.357001 - 22.553546999999998
Average (Standard dev.)	0.34427217 (±1.4535899)

• Symmetry: Space group: 1

Details

EMDB XML:

Map geometry	Axis order X Y Z Origin 0 0 0 Dimensions 270 270 270 Spacing 270 270 270
Cell	A=B=C: 220.31999 Å α=β=γ: 90.0 °

Supplemental data

Half map: half map 1

• File: emd_50440_half_map_1.map
• Annotation: half map 1

Half map: half map 2

• File: emd_50440_half_map_2.map
• Annotation: half map 2

Sample components

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

• Entire: Name: Amyloid fibrils of amyloid-beta(1-42)delta(19-24)

Components

• Tissue: Amyloid fibrils of amyloid-beta(1-42)delta(19-24)
  • Protein or peptide: Amyloid-beta precursor protein

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

• Supramolecule: Name: Amyloid fibrils of amyloid-beta(1-42)delta(19-24) / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
• Source (natural): Organism: unidentified (others)

Macromolecule #1: Amyloid-beta precursor protein

• Macromolecule: Name: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 20 / Enantiomer: LEVO
• Source (natural): Organism: Homo sapiens (human)
• Molecular weight: Theoretical: 3.81133 KDa

Sequence

String:

DAEFRHDSGY EVHHQKLVGS NKGAIIGLMV GGVVIA

UniProtKB: Amyloid-beta precursor protein

Experimental details

Structure determination

• Method: cryo EM
• Processing: helical reconstruction
• Aggregation state: filament

Sample preparation

• Buffer: pH: 2 ; Details: 30% (v/v) acetonitrile (AcN), 0.1% (v/v) trifluoroacetic acid (TFA) at pH 2 (~300 uM monomer concentration)
• Vitrification: Cryogen name: ETHANE

Electron microscopy

• Microscope: FEI TALOS ARCTICA
• Image recording: Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Ų
• Electron beam: Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
• Electron optics: Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
• Experimental equipment: Model: Talos Arctica / Image courtesy: FEI Company

Image processing

• Final reconstruction: Applied symmetry - Helical parameters - Δz: 4.7 Å; Applied symmetry - Helical parameters - Δ&Phi: -4.8 °; Applied symmetry - Helical parameters - Axial symmetry: C₁ (asymmetric); Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3) / Number images used: 133988
• CTF correction: Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
• Startup model: Type of model: OTHER; Details: an initial 3D reference was computed de novo from one large 2D class average assuming a helical rise of 4.75 Ang and a twist value calculated from the crossover-distance of each fibril observed from the larger box 2D class averages using the relion_helix_inimodel2d command
• Final angle assignment: Type: NOT APPLICABLE