Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Molecules, Год журнала: 2020, Номер 25(7), С. 1659 - 1659

Опубликована: Апрель 3, 2020

The structural polymorphism and the physiological pathophysiological roles of two important proteins, β-amyloid (Aβ) tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate monomeric Aβ has functions. Toxic oligomeric assemblies (AβOs) may decisive AD pathogenesis. polymorph fibrillar (fAβ) form very ordered cross-β structure is assumed to be non-toxic. Tau monomers also have several actions; however, their oligomerization leads toxic oligomers (TauOs). Further polymerization probably non-toxic structures, among others neurofibrillary tangles (NFTs). Their was determined by cryo-electron microscopy at atomic level. Both AβOs TauOs initiate neurodegenerative processes, interactions crosstalk determine changes AD. (perhaps AβO) prionoid character, they responsible for cell-to-cell spreading disease. extra- intracellular (and not previously hypothesized amyloid plaques NFTs) represent novel targets drug research.

Язык: Английский

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Amyloid aggregation simulations: challenges, advances and perspectives

Current Opinion in Structural Biology, Год журнала: 2020, Номер 67, С. 145 - 152

Опубликована: Дек. 3, 2020

Язык: Английский

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Disorder-to-order transition of the amyloid-β peptide upon lipid binding

Biophysical Chemistry, Год журнала: 2021, Номер 280, С. 106700 - 106700

Опубликована: Окт. 26, 2021

Язык: Английский

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Carbon quantum dots as ROS-generator and -scavenger: A comprehensive review

Dyes and Pigments, Год журнала: 2022, Номер 208, С. 110784 - 110784

Опубликована: Сен. 26, 2022

Язык: Английский

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Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment

Chemical Science, Год журнала: 2021, Номер 12(19), С. 6652 - 6669

Опубликована: Янв. 1, 2021

The amlyoid-β peptide (Aβ) is closely linked to the development of Alzheimer's disease. Molecular dynamics (MD) simulations have become an indispensable tool for studying behavior this at atomistic level. General key aspects MD are force field used modeling and its environment, which important accurate system interest, length simulations, determines whether or not equilibrium reached. In study we address these points by analyzing 30-μs acquired Aβ40 using seven different fields. We assess convergence based on various structural properties NMR fluorescence spectroscopic observables. Moreover, calculate Markov state models provide unprecedented view thermodynamics kinetics amyloid-β peptide. This further allows us answers pertinent questions, like: fields suitable Aβ? (a99SB-UCB a99SB-ILDN/TIP4P-D); what does Aβ really look like? (mostly extended disordered) and; how long it take attain equilibrium? (at least 20-30 μs). believe analyses presented in will a useful reference guide questions relating structure particular, extension other similar disordered proteins.

Язык: Английский

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A Hairpin Motif in the Amyloid-β Peptide Is Important for Formation of Disease-Related Oligomers

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(33), С. 18340 - 18354

Опубликована: Авг. 9, 2023

The amyloid-β (Aβ) peptide is associated with the development of Alzheimer's disease and known to form highly neurotoxic prefibrillar oligomeric aggregates, which are difficult study due their transient, low-abundance, heterogeneous nature. To obtain high-resolution information about oligomer structure dynamics as well relative populations assembly states, we here employ a combination native ion mobility mass spectrometry molecular simulations. We find that formation Aβ oligomers dependent on presence specific β-hairpin motif in sequence. Oligomers initially grow spherically but start extended linear aggregates at states larger than those tetramer. population could be notably increased by introducing an intramolecular disulfide bond, prearranges hairpin conformation, thereby promoting structures preventing conversion into mature fibrils. Conversely, truncating one β-strand-forming segments decreased propensity thus population, removed entirely, aggregation peptide. propose observed state related antiparallel sheet state, then nucleates amyloid state. These studies provide mechanistic understanding earliest steps suggest inhibition folding conformation viable strategy for reducing amount toxic oligomers.

Язык: Английский

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Liquid-Droplet-Mediated ATP-Triggered Amyloidogenic Pathway of Insulin-Derived Chimeric Peptides: Unraveling the Microscopic and Molecular Processes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(7), С. 4177 - 4186

Опубликована: Фев. 10, 2023

Disease-associated progression of protein dysfunction is typically determined by an interplay transition pathways leading to liquid–liquid phase separation (LLPS) and amyloid fibrils. As LLPS introduces another layer complexity into fibrillization metastable proteins, a need for tunable model systems study these intertwined processes has emerged. Here, we demonstrate the LLPS/fibrillization properties family chimeric peptides, ACC1–13Kn, in which highly amyloidogenic fragment insulin (ACC1–13) merged with oligolysine segments various lengths (Kn, n = 8, 16, 24, 32, 40). ACC1–13Kn are triggered ATP through Coulombic interactions Kn fragments. ACC1–13K8 ACC1–13K16 form fibrils after short lag without any evidence LLPS. However, case three longest triggers instantaneous followed disappearance droplets occurring in-phase formation The kinetics stability mature co-aggregates sensitive ionic strength, indicating that electrostatic play pivotal role selecting LLPS-fibrillization pathway. Densely packed characterize ACC1–13Kn–ATP render them hydrostatic pressure due solvent electrostriction, as demonstrated infrared spectroscopy. Using atomic force microscopy imaging rapidly frozen samples, early within single liquid droplets, starting at droplet/bulk interface bent fibers. A hypothetical molecular scenario underlying emergence LLPS-to-fibrils pathway system been put forward.

Язык: Английский

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Bioinspired crowding directs supramolecular polymerisation

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Фев. 25, 2023

Crowding effects are crucial to maintaining functionality in biological systems, but little is known about their role analogous artificial counterparts. Within the growing field of supramolecular polymer science, crowding have hitherto remained underappreciated. Herein, we show that exhibit strong and distinct control over kinetics, accessible pathways final outcomes polymerisation processes. In presence a pre-formed as agent, model dramatically changes its self-assembly behaviour undergoes morphological transformation from bundled fibres into flower-like hierarchical assemblies, despite no co-assembly taking place. Notably, this new pathway can only be accessed crowded environments when agent exhibits one-dimensional morphology. These results allow accessing diverse morphologies properties polymers pave way towards better understanding high-precision nature.

Язык: Английский

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A comprehensive review of protein misfolding disorders, underlying mechanism, clinical diagnosis, and therapeutic strategies

Ageing Research Reviews, Год журнала: 2023, Номер 90, С. 102017 - 102017

Опубликована: Июль 17, 2023

Язык: Английский

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New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5383 - 5383

Опубликована: Март 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Язык: Английский

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