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.

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 6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation

2021 ◽  
Author(s):  
Elina Berntsson ◽  
Suman Paul ◽  
Sabrina B. Sholts ◽  
Jüri Jarvet ◽  
Andreas Barth ◽  
...  
Keyword(s):  
Animal Studies ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Nutritional Supplement ◽  
Aβ Oligomers ◽  
Microscopy Imaging ◽  
Positive Effects ◽  
Age Related ◽  
Soluble Aβ Oligomers

AbstractAlzheimer’s disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-β (Aβ) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble Aβ oligomers appear to be highly neurotoxic. Cell and animal studies have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constituents of the ginger root, which in many cultures is a traditional nutritional supplement for memory enhancement. Here, we use biophysical experiments to characterize in vitro interactions between 6-gingerol and Aβ40 peptides. Our experiments with atomic force microscopy imaging, and nuclear magnetic resonance and Thioflavin-T fluorescence spectroscopy, show that the hydrophobic 6-gingerol molecule interferes with formation of Aβ40 aggregates, but does not interact with Aβ40 monomers. Thus, together with its favourable toxicity profile, 6-gingerol appears to display many of the desired properties of an anti-AD compound.

scholarly journals Different Aggregation Pathways and Structures for Aβ40 and Aβ42 Peptides

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 198
Author(s):  
Li Wang ◽  
Kilho Eom ◽  
Taeyun Kwon
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Vital Role ◽  
Aggregation Process ◽  
Aβ Peptides ◽  
Force Microscopy ◽  
Atomic Force ◽  
Different Shapes ◽  
In The Beginning ◽  
Self Aggregation

Self-aggregation of amyloid-β (Aβ) peptides has been known to play a vital role in the onset stage of neurodegenerative diseases, indicating the necessity of understanding the aggregation process of Aβ peptides. Despite previous studies on the aggregation process of Aβ peptides, the aggregation pathways of Aβ isoforms (i.e., Aβ40 and Aβ42) and their related structures have not been fully understood yet. Here, we study the aggregation pathways of Aβ40 and Aβ42, and the structures of Aβ40 and Aβ42 aggregates during the process, based on fluorescence and atomic force microscopy (AFM) experiments. It is shown that in the beginning of aggregation process for both Aβ40 and Aβ42, a number of particles (i.e., spherical oligomers) are formed. These particles are subsequently self-assembled together, resulting in the formation of different shapes of amyloid fibrils. Our finding suggests that the different aggregation pathways of Aβ isoforms lead to the amyloid fibrils with contrasting structure.

scholarly journals Dual Size-Dependent Effect of Fe3O4 Magnetic Nanoparticles Upon Interaction with Lysozyme Amyloid Fibrils: Disintegration and Adsorption

Nanomaterials ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 37 ◽  
Author(s):  
Natália Tomašovičová ◽  
Po-Sheng Hu ◽  
Cyun-Lun Zeng ◽  
Jozefína Majorošová ◽  
Katarína Zakutanská ◽  
...  
Keyword(s):  
Magnetic Nanoparticles ◽  
Amyloid Fibrils ◽  
Volume Concentration ◽  
Amyloid Β ◽  
Fe3o4 Magnetic Nanoparticles ◽  
Force Microscopy ◽  
Size Dependent ◽  
Egg White Lysozyme ◽  
Atomic Force ◽  
20 Nm

Nanomedicine compounds containing nanoparticles, such as iron oxides and gold, have been demonstrated to be effective in promoting different magnitudes of interaction with amyloid β fibrils, of which disintegrating or inhibiting effects are of great importance to treating fibrillary aggregation-induced neurological disorders such as Alzheimer’s disease. This research herein studies the interaction between lysozyme amyloid fibrils, a type of fibers derived from hen egg white lysozyme, and Fe3O4 magnetic nanoparticles (MNPs) of an assorted diameter sizes of 5 nm, 10 nm and 20 nm, using atomic force microscopy (AFM). Specifically, the effects of the sizes of negatively charged MNPs on the resultant amyloid fibrillary mixture was investigated. Our results of AFM images indicated that the interaction between MNPs and the fibrils commences immediately after adding MNPs to the fibril solution, and the actions of such MNPs-doped fibrillary interplay, either integration or segmentation, is strongly dependent on the size and volume concentration of MNPs. In the cases of 5 nm and 20 nm particles of equivalent volume concentration, the adsorption and agglomeration of MNPs onto the fibrillary surfaces was observed, whereas, interestingly, MNPs with diameter size of 10 nm enables segmentation of the slender fibrils into debris when a proper implemented volume concentration was found, which signifies utter destruction of the amyloid fibrillary structure.

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 Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ladan Amin ◽  
David A. Harris
Keyword(s):  
Amyloid Β ◽  
Super Resolution ◽  
Structural Motif ◽  
Aβ Oligomers ◽  
Surface Receptors ◽  
Molecular Features ◽  
Molecular Determinant ◽  
Receptor Interactions ◽  
Aβ Fibrils ◽  
Super Resolution Microscopy

AbstractSeveral cell-surface receptors for neurotoxic forms of amyloid-β (Aβ) have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating Alzheimer’s disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, PrPC, specifically inhibits the polymerization of Aβ fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Our results suggest that receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal.

scholarly journals Effects of tip-nanotube interactions on atomic force microscopy imaging of carbon nanotubes

Nano Research ◽  
2012 ◽  
Vol 5 (4) ◽  
pp. 235-247 ◽  
Author(s):  
Rouholla Alizadegan ◽  
Albert D. Liao ◽  
Feng Xiong ◽  
Eric Pop ◽  
K. Jimmy Hsia
Keyword(s):  
Carbon Nanotubes ◽  
Atomic Force Microscopy ◽  
Microscopy Imaging ◽  
Force Microscopy ◽  
Atomic Force ◽  
Atomic Force Microscopy Imaging
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