Cryo-EM structures of amyloid-β 42 filaments from human brains

Science, Год журнала: 2022, Номер 375(6577), С. 167 - 172

Опубликована: Янв. 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

Язык: Английский

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Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Cell, Год журнала: 2020, Номер 180(4), С. 633 - 644.e12

Опубликована: Фев. 1, 2020

Язык: Английский

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Amyloid structure determination in RELION-3.1

Acta Crystallographica Section D Structural Biology, Год журнала: 2020, Номер 76(2), С. 94 - 101

Опубликована: Янв. 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.

Язык: Английский

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A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain

Journal of Neurochemistry, Год журнала: 2020, Номер 154(6), С. 583 - 597

Опубликована: Март 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.

Язык: Английский

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Cryo-EM structures of tau filaments

Current Opinion in Structural Biology, Год журнала: 2020, Номер 64, С. 17 - 25

Опубликована: Июнь 27, 2020

Язык: Английский

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Structure of pathological TDP-43 filaments from ALS with FTLD

Nature, Год журнала: 2021, Номер 601(7891), С. 139 - 143

Опубликована: Дек. 8, 2021

Язык: Английский

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Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

eLife, Год журнала: 2022, Номер 11

Опубликована: Март 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.

Язык: Английский

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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

Chemical Reviews, Год журнала: 2021, Номер 121(3), С. 1845 - 1893

Опубликована: Янв. 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.

Язык: Английский

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Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Chemical Reviews, Год журнала: 2021, Номер 121(13), С. 8285 - 8307

Опубликована: Июнь 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.

Язык: Английский

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Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(4)

Опубликована: Янв. 11, 2021

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report the molecular structure a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), is derived from cortical tissue an AD patient seeded growth. The determined cryogenic electron microscopy (cryoEM) images, supplemented mass-per-length (MPL) measurements solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple patients had identified this polymorph as most prevalent brain-derived Aβ40 typical patients. structure, which has 2.8-Å resolution according standard criteria, differs qualitatively all previously described structures, both its conformations organization cross-β subunits. Unique features include twofold screw symmetry about growth axis, despite MPL value indicates three molecules per 4.8-Å β-sheet spacing, four-layered architecture, fully extended for central two layers. cryoEM density, data, data are consistent β-hairpin outer Knowledge development structure-specific amyloid imaging agents aggregation inhibitors greater diagnostic therapeutic utility.

Язык: Английский

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