CryoET of β-amyloid and tau within postmortem Alzheimer’s disease brain DOI Creative Commons

Madeleine A. G. Gilbert,

Nayab Fatima, Joshua Jenkins

et al.

Nature, Journal Year: 2024, Volume and Issue: 631(8022), P. 913 - 919

Published: July 10, 2024

Abstract A defining pathological feature of most neurodegenerative diseases is the assembly proteins into amyloid that form disease-specific structures 1 . In Alzheimer’s disease, this characterized by deposition β-amyloid and tau with conformations. The in situ structure human brain unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out cryo-electron tomography, we determined in-tissue architectures pathology a postmortem disease donor brain. plaques contained mixture fibrils, some which were branched, protofilaments, arranged parallel arrays lattice-like structures. Extracellular vesicles cuboidal particles defined non-amyloid constituents plaques. By contrast, inclusions formed clusters unbranched filaments. Subtomogram averaging cluster 136 filaments single tomogram revealed polypeptide backbone conformation filament polarity orientation paired helical within tissue. Filaments similar to each other, but different between clusters, showing heterogeneity spatially organized subcellular location. structural approaches outlined here for tissues have applications broad range diseases.

Language: Английский

Cryo-EM structures of amyloid-β 42 filaments from human brains DOI
Yang Yang, Diana Arseni, Wenjuan Zhang

et al.

Science, Journal Year: 2022, Volume and Issue: 375(6577), P. 167 - 172

Published: Jan. 14, 2022

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss memory and other cognitive functions the filamentous assembly Aβ tau in brain. The peptides into that end at residue 42 central event. Yang et al . used electron cryo–electron microscopy to determine structures from brain (see Perspective Willem Fändrich). They identified two types related S-shaped filaments, each consisting identical protofilaments. These will inform development better vitro animal models, inhibitors assembly, imaging agents with increased specificity sensitivity. —SMH

Language: Английский

Citations

360
Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains DOI Creative Commons

Tamta Arakhamia,

Christina E. Lee,

Yari Carlomagno

et al.

Cell, Journal Year: 2020, Volume and Issue: 180(4), P. 633 - 644.e12

Published: Feb. 1, 2020

Language: Английский

Citations

350
Amyloid structure determination in RELION-3.1 DOI Creative Commons
Sjors H. W. Scheres

Acta Crystallographica Section D Structural Biology, Journal Year: 2020, Volume and Issue: 76(2), P. 94 - 101

Published: Jan. 30, 2020

Helical reconstruction in RELION is increasingly being used to determine the atomic structures of amyloid filaments from electron cryo-microscopy (cryo-EM) images. However, because energy landscape refinements typically fraught with local optima, structure determination often difficult. This paper aims help users this process. It discusses aspects helical that are particularly relevant amyloids, it illustrates problem optima refinement and how detect them, introduces a new method calculate 3D initial models reference-free 2D class averages. By providing starting closer global optimum, makes easier. All methods described open-source distributed within RELION-3.1. Their use illustrated using publicly available data set on tau brain an individual Alzheimer's disease.

Language: Английский

Citations

231
Cryo-EM structures of tau filaments DOI
Sjors H. W. Scheres, Wenjuan Zhang, Benjamin Falcon

et al.

Current Opinion in Structural Biology, Journal Year: 2020, Volume and Issue: 64, P. 17 - 25

Published: June 27, 2020

Language: Английский

Citations

226
A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain DOI Open Access
Shaomin Li, Dennis J. Selkoe

Journal of Neurochemistry, Journal Year: 2020, Volume and Issue: 154(6), P. 583 - 597

Published: March 17, 2020

It is increasingly accepted that early cognitive impairment in Alzheimer's disease results considerable part from synaptic dysfunction caused by the accumulation of a range oligomeric assemblies amyloid β-protein (Aβ). Most studies have used synthetic Aβ peptides to explore mechanisms memory deficits rodent models, but recent work suggests isolated human (AD) brain tissue are far more potent and disease-relevant. Although reductionist experiments show oligomers impair plasticity neuronal viability, responsible only partly understood. Glutamatergic receptors, GABAergic nicotinic insulin cellular prion protein, inflammatory mediators, diverse signaling pathways all been suggested. Studies using AD brain-derived soluble suggest certain bioactive forms (principally small, diffusible oligomers) can disrupt plasticity, including binding plasma membranes changing excitatory-inhibitory balance, perturbing mGluR, PrP, other surface proteins, down-regulating glutamate transporters, causing spillover, activating extrasynaptic GluN2B-containing NMDA receptors. We synthesize these emerging data into mechanistic hypothesis for failure be modified as new knowledge added specific therapeutics developed.

Language: Английский

Citations

223
Structure of pathological TDP-43 filaments from ALS with FTLD DOI
Diana Arseni, Masato Hasegawa,

Alexey G. Murzin

et al.

Nature, Journal Year: 2021, Volume and Issue: 601(7891), P. 139 - 143

Published: Dec. 8, 2021

Language: Английский

Citations

218
Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy DOI Creative Commons
Sofia Lövestam,

Fujiet Adrian Koh,

Bart van Knippenberg

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: March 4, 2022

Abundant filamentous inclusions of tau are characteristic more than 20 neurodegenerative diseases that collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures amyloid filaments from human brain revealed distinct folds characterise many different diseases. A lack laboratory-based model systems to generate these has hampered efforts uncover the molecular mechanisms underlie Here, we report in vitro assembly conditions with recombinant replicate both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest post-translational modifications modulate filament assembly, previously observed additional densities AD CTE may arise presence inorganic salts, like phosphates sodium chloride. In into disease-relevant will facilitate studies determine their roles diseases, well development compounds specifically bind or prevent formation.

Language: Английский

Citations

211
Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes DOI
Danilo Milardi, Ehud Gazit, Sheena E. Radford

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(3), P. 1845 - 1893

Published: Jan. 11, 2021

The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures aggregation pathways of this hormone. Recent have reported the importance early oligomeric intermediates, many roles their interactions with lipid membrane, pH, insulin, zinc mechanism hIAPP. challenges posed by transient nature oligomers, structural heterogeneity, complex interaction membranes resulted development a wide range biophysical chemical approaches to characterize process. While cellular processes factors activating hIAPP-mediated cytotoxicity are still not clear, it recently been suggested that its impaired turnover processing proteasome autophagy may contribute significantly toward toxic and, eventually, death. Therefore, restoration proteostasis represent promising arena for design effective therapies. In review we discuss current knowledge pathology associated self-assembly point out opportunities therapy detailed biochemical, biophysical, understanding unveil.

Language: Английский

Citations

165
Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids DOI Creative Commons
Dieter Willbold, Birgit Strodel, Gunnar F. Schröder

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(13), P. 8285 - 8307

Published: June 17, 2021

This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures elucidated from various in vitro ex vivo obtained fibrils. In parallel, fibril formation has studied under highly artificial but comparatively reproducible conditions. The starts with a summary what is known speculated aggregation experiments. A partially hypothetic selection model be described that may suitable to explain why amyloid look way they do, particular, at least all so far reported high cryo-electron microscopy register, cross-β-sheet mostly consist two protofilaments twisted around each other. An intrinsic feature prion-like nature assemblies. Transferring point view situation not straightforward, hypothetic, leaves many open questions need addressed future.

Language: Английский

Citations

158
Age-dependent formation of TMEM106B amyloid filaments in human brains DOI Creative Commons
Manuel Schweighauser, Diana Arseni, Mehtap Bacioglu

et al.

Nature, Journal Year: 2022, Volume and Issue: 605(7909), P. 310 - 314

Published: March 28, 2022

Abstract Many age-dependent neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by abundant inclusions of amyloid filaments. Filamentous the proteins tau, amyloid-β, α-synuclein transactive response DNA-binding protein (TARDBP; also known TDP-43) most common 1,2 . Here we used structure determination cryogenic electron microscopy to show that residues 120–254 lysosomal type II transmembrane 106B (TMEM106B) form filaments in human brains. We determined structures TMEM106B from a number brain regions 22 individuals with deposits, including those resulting sporadic inherited tauopathies, amyloid-β amyloidoses, synucleinopathies TDP-43 proteinopathies, well frontal cortex 3 normal neurology no or only few deposits. observed three folds, clear relationships between folds diseases. correlated presence 29-kDa sarkosyl-insoluble fragment globular cytoplasmic inclusions, detected an antibody specific carboxy-terminal region TMEM106B. The identification brains older, but not younger, indicates they manner.

Language: Английский

Citations

149