Beta-Amyloid and Its Asp7 Isoform: Morphological and Aggregation Properties and Effects of Intracerebroventricular Administration DOI Creative Commons
Valeria Ushakova, Yana Zorkina, Olga Abramova

et al.

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(10), P. 1042 - 1042

Published: Oct. 21, 2024

Background/Objectives: One of the hallmarks Alzheimer’s disease (AD) is accumulation aggregated beta-amyloid (Aβ) protein in form senile plaques within brain tissue. Senile contain various post-translational modifications Aβ, including prevalent isomerization Asp7 residue. The isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis tissue transgenic mice. toxicity Aβ peptides may be partly mediated by their structure morphology. In this respect, study we analyzed structural aggregation characteristics isoform Aβ42 compared them those synthetic Aβ42. We also investigated effects intracerebroventricular (i.c.v.) administration these peptides, a method often used AD-like symptoms rodent models. Methods: Atomic force microscopy (AFM) was conducted compare morphological properties iso-Aβ42. i.c.v. stereotaxic proteins were assessed via behavioral analysis reactive oxygen species (ROS) estimation vivo using scanning ion-conductance microscope with confocal module. Results: AFM measurements revealed differences between two most notably soluble toxic oligomeric forms. iso-Aβ42 induced spatial memory deficits rats elevated oxidative stress levels vivo, suggesting potential ROS pathogenic mechanism peptide. Conclusions: findings support further investigation translational research on AD suggest its involvement neurodegenerative processes.

Language: Английский

Exploring the Potential of Aptamers in Targeting Neuroinflammation and Neurodegenerative Disorders: Opportunities and Challenges DOI Open Access
Anna Hau-Yee Kong,

Aston Jiaxi Wu,

Olivia Ka-Yi Ho

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(14), P. 11780 - 11780

Published: July 22, 2023

Neuroinflammation is the precursor for several neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), Parkinson’s (PD), and multiple sclerosis (MS). Targeting neuroinflammation has emerged a promising strategy to address wide range of CNS pathologies. These NDDs still present significant challenges in terms limited ineffective diagnosis treatment options, driving need explore innovative novel therapeutic alternatives. Aptamers are single-stranded nucleic acids that offer potential addressing these through diagnostic applications. In this review, we summarize aptamers inflammatory biomolecules, well cells NDDs. We also discussed short nucleotides Aptamer-Based Targeted Brain Delivery their unique features modifications, ability penetrate blood-brain barrier. Moreover, unprecedented opportunities substantial using agents, drug efficacy, safety considerations, pharmacokinetics, discussed. Taken together, review assesses pioneering approach target delivery

Language: Английский

Citations

8
Beyond N-Alkylation: Synthesis, Structure, and Function of N-Amino Peptides DOI
Isaac J. Angera,

Madison M. Wright,

Juan R. Del Valle

et al.

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: 57(9), P. 1287 - 1297

Published: April 16, 2024

ConspectusThe growing list of physiologically important protein–protein interactions (PPIs) has amplified the need for compounds to target topologically complex biomolecular surfaces. In contrast small molecules, peptide and protein mimics can exhibit three-dimensional shape complementarity across a large area thus have potential significantly expand "druggable" proteome. Strategies stabilize canonical secondary structures without sacrificing side-chain content are particularly useful in design peptide-based chemical probes therapeutics.Substitution backbone amide peptides represents subtle modification with profound effects on conformation stability. Studies focused N-alkylation already led broad-ranging applications peptidomimetic design. Inspired by nonribosomal natural products harboring N-oxidations, we envisioned that main-chain hydrazide hydroxamate bonds would impose distinct conformational preferences offer unique opportunities diversification. This Account describes our exploration N-amination as strategy stabilizing folds structure-based soluble amyloid mimics.We developed general synthetic protocol access N-amino (NAPs) solid support. an effort β-strand conformation, designed stitched peptidomimetics featuring covalent tethering substituent preceding residue side chain. Using combination NMR, X-ray crystallography, molecular dynamics simulations, discovered alone could β-hairpin multiple models folding. Our studies revealed NH2 NAPs participates cooperative noncovalent promote β-sheet structure. Cα-substituted α-hydrazino acids, found N-aminoglycine its N′-alkylated derivatives instead polyproline II (PPII) conformation. The reactivity hydrazides also allows late-stage macrocyclization, affording novel surrogates side-chain–backbone H-bonds.The pronounced propensity acids prompted us amyloidogenic proteins using NAP-based mimics. Backbone was render aggregation-prone lead sequences resistant proteolysis. Inhibitors Aβ tau identified through scanning blocked aggregation formation mature fibrils vitro. We further single-strand cross-β capable inhibiting prion-like cellular seeding activity recombinant patient-derived fibrils.Our establish valuable addition peptido- proteomimetic tool kit. α-Hydrazino show particular promise minimalist retain information. Late-stage derivatization provides facile entry into libraries backbone-edited peptides. anticipate will find development optimally constrained modulators PPIs.

Language: Английский

Citations

3
Cryo-EM structures of pathogenic fibrils and their impact on neurodegenerative disease research DOI
Tiffany W. Todd,

Naeyma N. Islam,

Casey Cook

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(14), P. 2269 - 2288

Published: June 3, 2024

Language: Английский

Citations

3
NMR studies of amyloid interactions DOI
David A. Middleton

Progress in Nuclear Magnetic Resonance Spectroscopy, Journal Year: 2024, Volume and Issue: 144-145, P. 63 - 96

Published: July 24, 2024

Language: Английский

Citations

3
Protein Condensates and Protein Aggregates: In Vitro, in the Cell, and In Silico DOI Creative Commons
Katja Venko, Eva Z̆erovnik

Frontiers in Bioscience-Landmark, Journal Year: 2023, Volume and Issue: 28(8), P. 183 - 183

Published: Aug. 28, 2023

Similar to other polypeptides and electrolytes, proteins undergo phase transitions, obeying physicochemical laws. They can liquid-to-gel liquid-to-liquid transitions. Intrinsically disordered are particularly susceptible separation. After a general introduction, the principles of in vitro studies protein folding, aggregation, condensation described. Numerous recent older have confirmed that process liquid-liquid separation (LLPS) leads various condensed bodies cells, which is one way cells manage stress. We review what known about aggregation cell, notwithstanding protective pathological roles aggregates. This includes membrane-less organelles cytotoxicity prefibrillar oligomers amyloid-forming proteins. then describe evaluate bioinformatic (in silico) methods for predicting aggregation-prone regions form amyloids, prions, condensates.

Language: Английский

Citations

8
Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots DOI
Douglas B. Kell, Etheresia Pretorius

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (also those originating viruses bacteria). presence inflammagens, pathological clotting occur, that results an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We provide evidence against entrapment model, noting clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant overlap normal plasma proteome correlation between abundance Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less such as adiponectin, periostin, von Willebrand Factor well represented. Using bioinformatic tools including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, their integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

Citations

2
Development of two-dimensional amyloid fibril/carboxymethyl cellulose hybrid membranes for effective adsorption of hexavalent chromium DOI
You-Ren Lai,

Xiao-Xuan Hou,

Su-Chun How

et al.

Journal of environmental chemical engineering, Journal Year: 2024, Volume and Issue: 12(6), P. 114134 - 114134

Published: Sept. 21, 2024

Language: Английский

Citations

2
Cholinium-Based Ionic Liquids Attenuate the Amyloid Fibril Formation of Lysozyme: A Greener Concept of Antiamyloidogenic Ionic Liquids DOI

Anamika Sindhu,

Rajender S. Varma, Pannuru Venkatesu

et al.

ACS Sustainable Chemistry & Engineering, Journal Year: 2022, Volume and Issue: 10(28), P. 9242 - 9253

Published: July 7, 2022

Amyloid fibrils share dominant β-sheet structures that form pathological deposits in human organs causing various debilitating neurodegenerative diseases such as type II diabetes, Huntington's, Alzheimer's, and Parkinson's diseases, thus, the treatment of these amyloid-based is a major overriding concern. Ionic liquids (ILs), being biocompatible solvent medium for proteins, have been introduced effective antiamyloidogenic agents to prevent fibrillation process; bio-derived cholinium-based ILs ([Chn] ILs) deserve special attention view their inhibitory action on protein amyloid formation enable restoration its biochemical function. Herein, four [Chn] ILs, namely cholinium acetate [Chn][Ac], bitartarate [Chn][Bit], chloride [Chn][Cl], dihydrogen phosphate [Chn][Dhp], vitro lysozyme (Lys) was investigated by applying ThT fluorescence, circular dichroism (CD), Fourier transform infrared (FT-IR) spectroscopy. Additionally, transmission electronic microscopy (TEM), dynamic light scattering (DLS), atomic force (AFM) measurements were also performed ascertain morphological changes. Interestingly, with incubation Lys without there substantial increase thioflavin T (ThT) fluorescence intensity Lys, confirming fibrillar aggregates. The results FT-IR UV-CD showed secondary structure retained presence [Chn][Bit] [Chn][DHP] which lost absence incubating conditions. It further inferred analysis via TEM, AFM, DLS through thermochemical formed, exhibit an increased propensity suppress mature fibrils. Overall, inhibition efficiency accredited cations well nature anions based Hofmeister series. present study offers deep insight into role controlling fibril proteins they may serve remediate diseases.

Language: Английский

Citations

10
The Action of Chemical Denaturants: From Globular to Intrinsically Disordered Proteins DOI Creative Commons
Antonella Paladino, Luigi Vitagliano, Giuseppe Graziano

et al.

Biology, Journal Year: 2023, Volume and Issue: 12(5), P. 754 - 754

Published: May 22, 2023

Proteins perform their many functions by adopting either a minimal number of strictly similar conformations, the native state, or vast ensemble highly flexible conformations. In both cases, structural features are influenced chemical environment. Even though plethora experimental studies have demonstrated impact denaturants on protein structure, molecular mechanism underlying action is still debated. present review, after brief recapitulation main data denaturants, we survey classical and more recent interpretations basis action. particular, highlight differences similarities that different classes proteins, i.e., globular, intrinsically disordered (IDP), amyloid-like assemblies. Particular attention has been given to IDPs, as unraveling fundamental importance in physiological processes. The role computation techniques expected play near future illustrated.

Language: Английский

Citations

5
β-Bracelets: Macrocyclic Cross-β Epitope Mimics Based on a Tau Conformational Strain DOI
Benjamin H. Rajewski, Kamlesh M. Makwana, Isaac J. Angera

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(42), P. 23131 - 23142

Published: Oct. 16, 2023

The aggregation of misfolded tau into neurotoxic fibrils is linked to the progression Alzheimer's disease (AD) and related tauopathies. Disease-associated conformations filamentous are characterized by hydrophobic interactions between side chains on unique distant β-strand modules within each protomer. Here, we report design diversity-oriented synthesis β-arch peptide macrocycles composed aggregation-prone PHF6 hexapeptide cross-β module specific AD fold. Termed "β-bracelets", these proteomimetics assemble in a sequence- macrocycle-dependent fashion, resulting amyloid-like that feature in-register parallel β-sheet structure. Backbone N-amination selected β-bracelet affords soluble inhibitors aggregation. We further demonstrate N-aminated block prion-like cellular seeding activity recombinant as well mature from patient extracts. These studies establish β-bracelets new class epitope mimics their utility rational molecules targeting amyloid propagation seeding.

Language: Английский

Citations

5