scholarly journals The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

2020 ◽  
Vol 21 (3) ◽  
pp. 1066
Author(s):  
Roberta Corti ◽  
Alysia Cox ◽  
Valeria Cassina ◽  
Luca Nardo ◽  
Domenico Salerno ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Force Microscopy ◽  
Atomic Force ◽  
Nanoparticle Surface ◽  
Afm Imaging ◽  
Aggregation Processes ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Binding Sequence ◽  
The Brain

The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit Aβ aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling Aβ aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed Aβ fibrils or to hinder the Aβ aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling Aβ aggregation processes.

scholarly journals Cytotoxic Aβ Protofilaments Are Generated in the Process of Aβ Fibril Disaggregation

2021 ◽  
Vol 22 (23) ◽  
pp. 12780
Author(s):  
Toshisuke Kaku ◽  
Kaori Tsukakoshi ◽  
Kazunori Ikebukuro
Keyword(s):  
Amyloid Fibrils ◽  
Epigallocatechin Gallate ◽  
Amyloid Β ◽  
Neural Cells ◽  
Aβ Oligomers ◽  
Microscopy Imaging ◽  
Force Microscopy ◽  
Atomic Force ◽  
Significant Research ◽  
Aβ Fibrils

Significant research on Alzheimer’s disease (AD) has demonstrated that amyloid β (Aβ) oligomers are toxic molecules against neural cells. Thus, determining the generation mechanism of toxic Aβ oligomers is crucial for understanding AD pathogenesis. Aβ fibrils were reported to be disaggregated by treatment with small compounds, such as epigallocatechin gallate (EGCG) and dopamine (DA), and a loss of fibril shape and decrease in cytotoxicity were observed. However, the characteristics of intermediate products during the fibril disaggregation process are poorly understood. In this study, we found that cytotoxic Aβ aggregates are generated during a moderate disaggregation process of Aβ fibrils. A cytotoxicity assay revealed that Aβ fibrils incubated with a low concentration of EGCG and DA showed higher cytotoxicity than Aβ fibrils alone. Atomic force microscopy imaging and circular dichroism spectrometry showed that short and narrow protofilaments, which were highly stable in the β-sheet structure, were abundant in these moderately disaggregated samples. These results indicate that toxic Aβ protofilaments are generated during disaggregation from amyloid fibrils, suggesting that disaggregation of Aβ fibrils by small compounds may be one of the possible mechanisms for the generation of toxic Aβ aggregates in the brain.

Specific keratinase derived designer peptides potently inhibit Aβ aggregation resulting in reduced neuronal toxicity and apoptosis

2019 ◽  
Vol 476 (12) ◽  
pp. 1817-1841 ◽  
Author(s):  
Rinky Rajput ◽  
Balasubramani G L ◽  
Ankit Srivastava ◽  
Divya Wahi ◽  
Nidhi Shrivastava ◽  
...  
Keyword(s):  
Self Assembly ◽  
Amyloid Β ◽  
Md Simulations ◽  
New Approach ◽  
Force Microscopy ◽  
Atomic Force ◽  
Aromatic Interactions ◽  
Neuronal Toxicity ◽  
Aβ Aggregation ◽  
Amyloid Diseases

Abstract Compelling evidence implicates self-assembly of amyloid-β (Aβ1–42) peptides into soluble oligomers and fibrils as a major underlying event in Alzheimer's disease (AD) pathogenesis. Herein, we employed amyloid-degrading keratinase (kerA) enzyme as a key Aβ1–42-binding scaffold to identify five keratinase-guided peptides (KgPs) capable of interacting with and altering amyloidogenic conversion of Aβ1–42. The KgPs showed micromolar affinities with Aβ1–42 and abolished its sigmoidal amyloidogenic transition, resulting in abrogation of fibrillogenesis. Comprehensive assessment using dynamic light scattering (DLS), atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy showed that KgPs induced the formation of off-pathway oligomers comparatively larger than the native Aβ1–42 oligomers but with a significantly reduced cross-β signature. These off-pathway oligomers exhibited low immunoreactivity against oligomer-specific (A11) and fibril-specific (OC) antibodies and rescued neuronal cells from Aβ1–42 oligomer toxicity as well as neuronal apoptosis. Structural analysis using molecular docking and molecular dynamics (MD) simulations showed two preferred KgP binding sites (Lys16–Phe20 and Leu28–Val39) on the NMR ensembles of monomeric and fibrillar Aβ1–42, indicating an interruption of crucial hydrophobic and aromatic interactions. Overall, our results demonstrate a new approach for designing potential anti-amyloid molecules that could pave way for developing effective therapeutics against AD and other amyloid diseases.

scholarly journals Polyphenols Modulate Alzheimer’s Amyloid Beta Aggregation in a Structure-Dependent Manner

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 756 ◽  
Author(s):  
Huong Phan ◽  
Kaouthar Samarat ◽  
Yuzuru Takamura ◽  
Auriane Azo-Oussou ◽  
Yasutaka Nakazono ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Self Assembly ◽  
Structural Features ◽  
Hydroxyl Groups ◽  
Dependent Manner ◽  
Force Microscopy ◽  
Atomic Force ◽  
Aggregation Property ◽  
Aβ Aggregation ◽  
Aβ Fibrils

Some polyphenols, which are common natural compounds in fruits, vegetables, seeds, and oils, have been considered as potent inhibitors of amyloid beta (Aβ) aggregation, one critical pathogenic event in Alzheimer’s disease (AD). However, the mechanisms by which polyphenols affect aggregation are not fully understood. In this study, we aimed to investigate the effect of two classes of polyphenols (flavonoids and stilbenes) on the self-assembly of Aβ_42, in particular, how this relates to structure. We found that the flavonoids gallocatechin gallate (GCG) and theaflavin (TF) could completely inhibit Aβ aggregation, while two stilbenes, resveratrol and its glucoside derivative piceid, could also suppress Aβ aggregation, but to a much lesser extent. Intriguingly, resveratrol accelerated the formation of Aβ fibrils before its decreasing effect on fibrillation was detected. Atomic force microscopy (AFM) images showed a huge mass of long and thin Aβ fibrils formed in the presence of resveratrol. Although the morphology was the same in the presence of piceid, the fibrils were sparse in the presence of picead. In the presence of flavonoids, Aβ morphology was unchanged from prior to incubation (0 h), in agreement with amyloid beta kinetics analysis using thioflavin-T fluorescence assay. The electrochemical data showed a higher ability of GCG and TF to interact with Aβ than resveratrol and piceid, which could be attributed to the presence of more aromatic rings and hydroxyl groups. In addition, the two flavonoids exhibited a similar propensity for Aβ aggregation, despite having some differences in their structure. However, in the case of stilbenes, the addition of a glucoside at C-7 slightly decreased anti-Aβ aggregation property compared to resveratrol. These findings contribute to a better understanding of the essential structural features of polyphenols required for inhibiting Aβ aggregation, and the possible mechanisms for modulating aggregation.

Brittle Behaviour in Aspirin Crystals: Evidence of Spalling Fracture

2020 ◽  
Author(s):  
Benjamin P. A. Gabriele ◽  
Craig J. Williams ◽  
Douglas Stauffer ◽  
Brian Derby ◽  
Aurora J. Cruz-Cabeza
Keyword(s):  
Surface Roughness ◽  
Atomic Force Microscopy ◽  
Single Crystals ◽  
Spalling Fracture ◽  
Force Microscopy ◽  
Atomic Force ◽  
Afm Imaging

<div> <div> <div> <p>Single crystals of aspirin form I were cleaved and indented on their dominant face. Upon inspection, it was possible to observe strongly anisotropic shallow lateral cracks due to the extreme low surface roughness after cleavage. Atomic Force Microscopy (AFM) imaging showed spalling fractures nucleating from the indent corners, forming terraces with a height of one or two interplanar spacings d100. The formation of such spalling fractures in aspirin was rationalised using basic calculations of attachment energies, showing how (100) layers are poorly bonded when compared to their relatively higher intralayer bonding. An attempt at explaining the preferential propagation of these fractures along the [010] direction is discussed. </p> </div> </div> </div>

Brittle Behaviour in Aspirin Crystals: Evidence of Spalling Fracture

2020 ◽  
Author(s):  
Benjamin P. A. Gabriele ◽  
Craig J. Williams ◽  
Douglas Stauffer ◽  
Brian Derby ◽  
Aurora J. Cruz-Cabeza
Keyword(s):  
Surface Roughness ◽  
Atomic Force Microscopy ◽  
Single Crystals ◽  
Spalling Fracture ◽  
Force Microscopy ◽  
Atomic Force ◽  
Afm Imaging

<div> <div> <div> <p>Single crystals of aspirin form I were cleaved and indented on their dominant face. Upon inspection, it was possible to observe strongly anisotropic shallow lateral cracks due to the extreme low surface roughness after cleavage. Atomic Force Microscopy (AFM) imaging showed spalling fractures nucleating from the indent corners, forming terraces with a height of one or two interplanar spacings d100. The formation of such spalling fractures in aspirin was rationalised using basic calculations of attachment energies, showing how (100) layers are poorly bonded when compared to their relatively higher intralayer bonding. An attempt at explaining the preferential propagation of these fractures along the [010] direction is discussed. </p> </div> </div> </div>

scholarly journals Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

2021 ◽  
Vol 22 (3) ◽  
pp. 1225
Author(s):  
Ziao Fu ◽  
William E. Van Nostrand ◽  
Steven O. Smith
Keyword(s):  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Aβ Oligomers ◽  
Dominant Component ◽  
Fibril Structure ◽  
Predominant Component ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Soluble Aβ Oligomers ◽  
Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

scholarly journals Atomic force microscopy analysis of native infectious and inactivated SARS-CoV-2 virions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sébastien Lyonnais ◽  
Mathilde Hénaut ◽  
Aymeric Neyret ◽  
Peggy Merida ◽  
Chantal Cazevieille ◽  
...  
Keyword(s):  
Atomic Force Microscopy ◽  
Native Conformation ◽  
Force Microscopy ◽  
Enveloped Virus ◽  
Atomic Force ◽  
Afm Imaging ◽  
Level 3 ◽  
Microscopy Analysis ◽  
Virus Morphology ◽  
Nanoscale Level

AbstractSARS-CoV-2 is an enveloped virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. Here, single viruses were analyzed by atomic force microscopy (AFM) operating directly in a level 3 biosafety (BSL3) facility, which appeared as a fast and powerful method to assess at the nanoscale level and in 3D infectious virus morphology in its native conformation, or upon inactivation treatments. AFM imaging reveals structurally intact infectious and inactivated SARS-CoV-2 upon low concentration of formaldehyde treatment. This protocol combining AFM and plaque assays allows the preparation of intact inactivated SARS-CoV-2 particles for safe use of samples out of level 3 laboratory to accelerate researches against the COVID-19 pandemic. Overall, we illustrate how adapted BSL3-AFM is a remarkable toolbox for rapid and direct virus analysis based on nanoscale morphology.

scholarly journals Borrelidin from Saltern-Derived Halophilic Nocardiopsis sp. Dissociates Amyloid-β and Tau Fibrils

2020 ◽  
pp. 1-7
Author(s):  
Jisu Shin ◽  
Seung-Hoon Yang ◽  
Young Eun Du ◽  
Keunwan Park ◽  
DaWon Kim ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Thioflavin T ◽  
Drug Candidate ◽  
Ht22 Cells ◽  
Aβ Aggregation ◽  
Actinomycete Strain ◽  
Direct Dissociation ◽  
Aβ Fibrils ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-β (Aβ) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aβ or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aβ and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. Objective: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aβ and tau aggregates through in vitro assessments. Methods: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aβ fibrils. Then, anti-cytotoxic, anti-Aβ, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. Results: When HT22 cells were exposed to Aβ aggregates, the treatment of borrelidins alleviates the Aβ-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aβ aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aβ aggregates but also directly regulates tau aggregation. Conclusion: Borrelidin dissociates insoluble Aβ and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aβ or anti-tau immunotherapy for clearance of both aggregates.

Atomic force microscopy (AFM) imaging suggests that stromal interaction molecule 1 (STIM1) binds to Orai1 with sixfold symmetry

FEBS Letters ◽  
2014 ◽  
Vol 588 (17) ◽  
pp. 2874-2880 ◽  
Author(s):  
Dilshan Balasuriya ◽  
Shyam Srivats ◽  
Ruth D. Murrell-Lagnado ◽  
J. Michael Edwardson
Keyword(s):  
Atomic Force Microscopy ◽  
Force Microscopy ◽  
Stromal Interaction Molecule 1 ◽  
Atomic Force ◽  
Afm Imaging ◽  
Sixfold Symmetry

Imaging of Xenopus laevis Oocyte Plasma Membrane in Physiological-Like Conditions by Atomic Force Microscopy

2013 ◽  
Vol 19 (5) ◽  
pp. 1358-1363 ◽  
Author(s):  
Massimo Santacroce ◽  
Federica Daniele ◽  
Andrea Cremona ◽  
Diletta Scaccabarozzi ◽  
Michela Castagna ◽  
...  
Keyword(s):  
Atomic Force Microscopy ◽  
Plasma Membrane ◽  
High Resolution ◽  
Membrane Proteins ◽  
Xenopus Laevis ◽  
Functional Study ◽  
Xenopus Laevis Oocyte ◽  
Force Microscopy ◽  
Atomic Force ◽  
Afm Imaging

AbstractXenopus laevis oocytes are an interesting model for the study of many developmental mechanisms because of their dimensions and the ease with which they can be manipulated. In addition, they are widely employed systems for the expression and functional study of heterologous proteins, which can be expressed with high efficiency on their plasma membrane. Here we applied atomic force microscopy (AFM) to the study of the plasma membrane of X. laevis oocytes. In particular, we developed and optimized a new sample preparation protocol, based on the purification of plasma membranes by ultracentrifugation on a sucrose gradient, to perform a high-resolution AFM imaging of X. laevis oocyte plasma membrane in physiological-like conditions. Reproducible AFM topographs allowed visualization and dimensional characterization of membrane patches, whose height corresponds to a single lipid bilayer, as well as the presence of nanometer structures embedded in the plasma membrane and identified as native membrane proteins. The described method appears to be an applicable tool for performing high-resolution AFM imaging of X. laevis oocyte plasma membrane in a physiological-like environment, thus opening promising perspectives for studying in situ cloned membrane proteins of relevant biomedical/pharmacological interest expressed in this biological system.

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