Nanozyme sensor array based on manganese dioxide for the distinction between multiple amyloid β peptides and their dynamic aggregation process

2021 ◽  
pp. 113881
Author(s):  
Shun Hu ◽  
Changwen Yang ◽  
Yanqing Li ◽  
Qingming Luo ◽  
Haiming Luo
Keyword(s):  
Manganese Dioxide ◽  
Sensor Array ◽  
Amyloid Β ◽  
Aggregation Process

scholarly journals β-Hairpin mimics containing a piperidine–pyrrolidine scaffold modulate the β-amyloid aggregation process preserving the monomer species

2017 ◽  
Vol 8 (2) ◽  
pp. 1295-1302 ◽  
Author(s):  
S. Pellegrino ◽  
N. Tonali ◽  
E. Erba ◽  
J. Kaffy ◽  
M. Taverna ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Protein Protein Interactions ◽  
Β Amyloid

Acyclic β-hairpins designed on oligomeric and fibril structures of Aβ1–42 disrupt protein–protein interactions mediating amyloid β-peptide aggregation.

scholarly journals Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

2019 ◽  
Author(s):  
Siddhartha Banerjee ◽  
Mohtadin Hashemi ◽  
Karen Zagorski ◽  
Yuri L. Lyubchenko
Keyword(s):  
Self Assembly ◽  
Lipid Membranes ◽  
Membrane Surface ◽  
Amyloid Β ◽  
Test Tube ◽  
Aggregation Process ◽  
Self Assembling ◽  
Nanoscale Aggregates

AbstractThe assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid β (Aβ) proteins is considered as a major cause for the development of Alzheimer’s disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that Aβ42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein. As a result, the misfolded Aβ42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.

scholarly journals Reproducibility Problems of Amyloid-β Self-Assembly and How to Deal With Them

2021 ◽  
Vol 8 ◽  
Author(s):  
Peter Faller ◽  
Christelle Hureau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Test Tube ◽  
The Self ◽  
Aggregation Process ◽  
Self Assembled

The self-assembly of peptides and proteins into amyloid fibrils and other aggregates are linked to several diseases. One of the most studied cases is the peptide amyloid-β (Aβ), found self-assembled in Alzheimer's disease patients' brains. In test tubes, assays with chemically synthesized or recombinant Aβ are widely investigated to understand the aggregation process and to find modulators, which could be of therapeutic interest. Experience over more than a decade in our laboratory through discussions with colleagues, expertly studying the literature, and as reviewers revealed to us the widely encountered difficulty to control the aggregation and obtain reproducible results in the test tube. However, this issue is scarcely reported and discussed in the publications, which we think hampers strongly the progress in this field and can deceive newcomers. Here, we describe the difficulty and potential reasons to obtain reproducible aggregation data and propose some guidelines for working with it.

scholarly journals Two step aggregation kinetics of Amyloid-β proteins from fractal analysis

2021 ◽  
Author(s):  
Soham Mukhopadhyay ◽  
Subhas C. Bera ◽  
Kabir Ramola
Keyword(s):  
Fractal Dimension ◽  
Single Molecule ◽  
Amyloid Fibrils ◽  
Linear Growth ◽  
Imaging Techniques ◽  
Nonlinear Differential Equations ◽  
Amyloid Β ◽  
Aggregation Process ◽  
Mean Field Model ◽  
Tirf Microscopy

Self-aggregation in proteins has long been studied and modeled due to its ubiquity and importance in many biological contexts. Several models propose a two step aggregation mechanism, consisting of linear growth of fibrils and branch formation. Single molecule imaging techniques such as total internal reflection fluorescence (TIRF) microscopy can provide direct evidence of such mechanisms, however, analyzing such large datasets is challenging. In this paper, we analyze for the first time, images of growing amyloid fibrils obtained from TIRF microscopy using the techniques of fractal geometry, which provides a natural framework to disentangle the two types of growth mechanisms at play. We find that after an initial linear growth phase, identified by a plateau in the average fractal dimension with time, the occurrence of branching events leads to a further increase in the fractal dimension with a final saturation value ≈ 2. We also simulate the aggregation process using the identified linear growth and secondary nucleation mechanisms, using an event driven algorithm. We theoretically model this system using a set of coupled nonlinear differential equations describing a mean field model for branching and linear growth, which we use to characterize the growth process observed in simulations as well as experiments. Finally, we provide estimates for the parameter regimes that govern the two step aggregation process observed in experiments.

scholarly journals Mechanism of amyloid protein aggregation and the role of inhibitors

2019 ◽  
Vol 91 (2) ◽  
pp. 211-229 ◽  
Author(s):  
Sara Linse
Keyword(s):  
Total Concentration ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aggregation Process ◽  
Secondary Nucleation ◽  
Toxic Species ◽  
Primary Nucleation ◽  
Effective Inhibition ◽  
Aβ Aggregation

Abstract Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection of this process with Alzheimer’s disease. Traditionally, inhibitors were developed with an aim to retard the overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, the microscopic steps underlying the aggregation process are identified, and it is established which of these step(s) lead to neurotoxicity. Inhibitors are then derived to specifically target steps involved in toxicity. The Aβ aggregation process is composed of at minimum three microscopic steps: primary nucleation of monomers only, secondary nucleation of monomers on fibril surface, and elongation of fibrils by monomer addition. The vast majority of toxic species are generated from the secondary nucleation process: this may be a key process to inhibit in order to limit toxicity. Inhibition of primary nucleation, which delays the emergence of toxic species without affecting their total concentration, may also be effective. Inhibition of elongation may instead increase the toxicity over time. Here we briefly review findings regarding secondary nucleation of Aβ, its dominance over primary nucleation, and attempts to derive inhibitors that specifically target secondary nucleation with an aim to limit toxicity.

scholarly journals Structure and topology of the non-amyloid-β component fragment of human α-synuclein bound to micelles: Implications for the aggregation process

2006 ◽  
Vol 15 (6) ◽  
pp. 1408-1416 ◽  
Author(s):  
Marco Bisaglia ◽  
Alessandra Trolio ◽  
Massimo Bellanda ◽  
Elisabetta Bergantino ◽  
Luigi Bubacco ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Aggregation Process ◽  
And Topology

Specific Binding of a β-Cyclodextrin Dimer to the Amyloid β Peptide Modulates the Peptide Aggregation Process

Biochemistry ◽  
2012 ◽  
Vol 51 (21) ◽  
pp. 4280-4289 ◽  
Author(s):  
Anna Wahlström ◽  
Risto Cukalevski ◽  
Jens Danielsson ◽  
Jüri Jarvet ◽  
Hideki Onagi ◽  
...  
Keyword(s):  
Specific Binding ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Aggregation Process ◽  
Cyclodextrin Dimer

Aggregation of amyloids in a cellular context: modelling and experiment

2011 ◽  
Vol 438 (3) ◽  
pp. 415-426 ◽  
Author(s):  
Ran Friedman
Keyword(s):  
Lipid Membranes ◽  
Amyloid Β ◽  
Integrative Approach ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Molecular Events ◽  
Context Modelling ◽  
Wide Range ◽  
Recent Developments

Amyloid-related diseases are a group of illnesses in which an abnormal accumulation of proteins into fibrillar structures is evident. Results from a wide range of studies, ranging from identification of amyloid-β dimers in the brain to biophysical characterization of the interactions between amyloidogenic peptides and lipid membranes during fibril growth shed light on the initial events which take place during amyloid aggregation. Accounts of fibril disaggregation and formation of globular aggregates due to interactions with lipids or fatty acids further demonstrate the complexity of the aggregation process and the difficulty to treat amyloid-related diseases. There is an inherent difficulty in generalizing from studies of aggregation in vitro, but the involvement of too many cellular components limits the ability to follow amyloid aggregation in a cellular (or extracellular) context. Fortunately, the development of experimental methods to generate stable globular aggregates suggests new means of studying the molecular events associated with amyloid aggregation. Furthermore, simulation studies enable deeper understanding of the experimental results and provide useful predictions that can be tested in the laboratory. Computer simulations can nowadays provide molecular or even atomistic details that are experimentally not available or very difficult to obtain. In the present review, recent developments on modelling and experiments of amyloid aggregation are reviewed, and an integrative account on how isolated interactions (as observed in vitro and in silico) combine during the course of amyloid-related diseases is presented. Finally, it is argued that an integrative approach is necessary to get a better understanding of the protein aggregation process.

Investigation of the Aggregation Process of Amyloid-β-(16-22) Peptides and the Dissolution of Intermediate Aggregates

Langmuir ◽  
2014 ◽  
Vol 30 (11) ◽  
pp. 3170-3175 ◽  
Author(s):  
Dongdong Lin ◽  
Yin Luo ◽  
Shan Wu ◽  
Qianqian Ma ◽  
Guanghong Wei ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Aggregation Process

scholarly journals Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

2021 ◽  
Vol 15 ◽  
Author(s):  
Tatsuya Ikenoue ◽  
Francesco A. Aprile ◽  
Pietro Sormanni ◽  
Michele Vendruscolo
Keyword(s):  
Drug Discovery ◽  
Molecular Recognition ◽  
Kinetic Analysis ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Formation ◽  
Aggregation Process ◽  
Structural Studies ◽  
Recognition Ability ◽  
Amyloidogenic Region

There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.

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