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- EMDB-15771: Type II amyloid-beta 42 filaments from high-spin supernatants of ... -

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Basic information

Entry
Database: EMDB / ID: EMD-15771
TitleType II amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42
Map data
Sample
  • Tissue: Type II amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
    • Protein or peptide: Amyloid-beta precursor protein
Keywordsamyloid / filaments / Abeta42 / amyloid-beta / cryo-EM / PROTEIN FIBRIL
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / axon midline choice point recognition ...amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / axon midline choice point recognition / regulation of synapse structure or activity / hippocampal neuron apoptotic process / 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 / PTB domain binding / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / Golgi-associated vesicle / astrocyte projection / Lysosome Vesicle Biogenesis / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / TRAF6 mediated NF-kB activation / positive regulation of protein metabolic process / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / Advanced glycosylation endproduct receptor signaling / transition metal ion binding / The NLRP3 inflammasome / main axon / regulation of multicellular organism growth / modulation of excitatory postsynaptic potential / intracellular copper ion homeostasis / ECM proteoglycans / regulation of presynapse assembly / positive regulation of T cell migration / response to insulin-like growth factor stimulus / neuronal dense core vesicle / Purinergic signaling in leishmaniasis infection / cellular response to manganese ion / Notch signaling pathway / positive regulation of chemokine production / swimming behavior / extracellular matrix organization / neuron projection maintenance / clathrin-coated pit / astrocyte activation / axonogenesis / positive regulation of mitotic cell cycle / Mitochondrial protein degradation / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / platelet alpha granule lumen / response to interleukin-1 / regulation of neuron apoptotic process / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / endosome lumen / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / dendritic shaft / central nervous system development / protein serine/threonine kinase binding / positive regulation of interleukin-1 beta production / learning / adult locomotory behavior / Post-translational protein phosphorylation / serine-type endopeptidase inhibitor activity / locomotory behavior / microglial cell activation / cellular response to nerve growth factor stimulus / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / regulation of long-term neuronal synaptic plasticity / synapse organization / visual learning / recycling endosome / response to lead ion / positive regulation of JNK cascade / positive regulation of interleukin-6 production / Golgi lumen / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / endocytosis / positive regulation of tumor necrosis factor production / neuron projection development / positive regulation of inflammatory response / calcium ion transport / Platelet degranulation / regulation of translation / heparin binding / regulation of gene expression
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, heparin-binding / Amyloid A4 N-terminal heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide ...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
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsYang Y / Stern MA / Meunier LA / Liu W / Cai YQ / Ericsson M / Liu L / Selkoe JD / Goedert M / Scheres HWS
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Citation
Journal: Neuron / Year: 2023
Title: Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains.
Authors: Andrew M Stern / Yang Yang / Shanxue Jin / Keitaro Yamashita / Angela L Meunier / Wen Liu / Yuqi Cai / Maria Ericsson / Lei Liu / Michel Goedert / Sjors H W Scheres / Dennis J Selkoe /
Abstract: Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed ...Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.
#1: Journal: Biorxiv / Year: 2022
Title: Abundant A beta fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains
Authors: Stern AM / Yang Y / Meunier AL / Liu W / Cai Y / Ericsson M / Liu L / Goedert M / Scheres SHW / Selkoe DJ
History
DepositionSep 6, 2022-
Header (metadata) releaseNov 2, 2022-
Map releaseNov 2, 2022-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15771.png

Downloads & links

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Map

FileDownload / File: emd_15771.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.736 Å		0.83 Å/pix.
x 256 pix.
= 212.736 Å		0.83 Å/pix.
x 256 pix.
= 212.736 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.831 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0075
Minimum - Maximum-0.011013753 - 0.021757321
Average (Standard dev.)0.00015564695 (±0.0012345087)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.736 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_15771_msk_1.map
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Half map: #2

Fileemd_15771_half_map_1.map
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Half map: #1

Fileemd_15771_half_map_2.map
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Sample components

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Entire : Type II amyloid-beta 42 filaments in soluble high-molecular weigh...

EntireName: Type II amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
Components
  • Tissue: Type II amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
    • Protein or peptide: Amyloid-beta precursor protein

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Supramolecule #1: Type II amyloid-beta 42 filaments in soluble high-molecular weigh...

SupramoleculeName: Type II amyloid-beta 42 filaments in soluble high-molecular weight aggregate fractions extracted from Alzheimer's disease brain
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Amyloid-beta precursor protein

MacromoleculeName: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.520087 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV IA

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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k 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: 2.4 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: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.8 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 14740
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7q4m


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-8azt:
Type II amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42

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