Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (Aβ) peptide in monomeric form: Low pH was found to reduce Aβ/Cu(II) binding affinity

2013 ◽  
Vol 120 ◽  
pp. 18-23 ◽  
Author(s):  
Joel Lindgren ◽  
Patrik Segerfeldt ◽  
Sabrina B. Sholts ◽  
Astrid Gräslund ◽  
Amelie Eriksson Karlström ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Amyloid Beta ◽  
Low Ph ◽  
Aβ Peptide ◽  
Monomeric Form ◽  
Affibody Molecules

Electrochemistry of Alzheimer Disease Amyloid Beta Peptides

2018 ◽  
Vol 25 (33) ◽  
pp. 4066-4083 ◽  
Author(s):  
Ana-Maria Chiorcea-Paquim ◽  
Teodor Adrian Enache ◽  
Ana Maria Oliveira-Brett
Keyword(s):  
Amino Acid ◽  
Amyloid Beta ◽  
Biological Fluids ◽  
Electron Transfer Reaction ◽  
Random Coil ◽  
Sequence Length ◽  
Dependent Manner ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Α Helix

Alzheimer’s disease (AD) is a widespread form of dementia that is estimated to affect 44.4 million people worldwide. AD pathology is closely related to the accumulation of amyloid beta (Aβ) peptides in fibrils and plagues, the small oligomeric intermediate species formed during the Aβ peptides aggregation presenting the highest neurotoxicity. This review discusses the recent advances on the Aβ peptides electrochemical characterization. The Aβ peptides oxidation at a glassy carbon electrode occurs in one or two steps, depending on the amino acid sequence, length and content. The first electron transfer reaction corresponds to the tyrosine Tyr10 amino acid residue oxidation, and the second to all three histidine (His6, His13 and His14) and one methionine (Met35) amino acid residues. The Aβ peptides aggregation and amyloid fibril formation are electrochemically detected via the electroactive amino acids oxidation peak currents decrease that occurs in a time dependent manner. The Aβ peptides redox behaviour is correlated with changes in the adsorption morphology from initially random coiled structures, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to aggregates, protofibrils and two types of fibrils, corresponding to the Aβ peptides in a β-sheet configuration, observed by atomic force microscopy. Electrochemical studies of Aβ peptides aggregation, mediated by the interaction with metal ions, particularly zinc, copper and iron, and different methodologies concerning the detection of Aβ peptide biomarkers of AD in biological fluids, using electrochemical biosensors, are also discussed.

scholarly journals Analysis of a Highly Flexible Conformational Immunogenic Domain A in Hepatitis C Virus E2

2005 ◽  
Vol 79 (21) ◽  
pp. 13199-13208 ◽  
Author(s):  
Zhen-Yong Keck ◽  
Ta-Kai Li ◽  
Jinming Xia ◽  
Birke Bartosch ◽  
François-Loïc Cosset ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Binding Affinity ◽  
Structural Changes ◽  
Low Ph ◽  
Antibody Binding ◽  
Spatial Proximity ◽  
Neutralizing Activity ◽  
Isolation And Characterization ◽  
Structural And Functional Properties

ABSTRACT Hepatitis C (HCV) E2 glycoprotein is involved in virus attachment and entry, and its structural organization is largely unknown. Characterization of a panel of human monoclonal antibodies (HMAbs) to HCV by competition studies has led to an immunogenic organization model of E2 with three domains designated A, B, and C and epitopes in each domain having similar structural and functional properties. Domain A contains nonneutralizing epitopes, and domains B and C contain neutralizing epitopes. The isolation and characterization of three new HMAbs within domain A for a total of six provide support for this model. All six domain A HMAbs do not neutralize HCV retroviral pseudotype particle (HCVpp) infection on Huh-7 cells, and all six HMAbs have similar binding affinity and maximum binding, B max, a relative indicator of epitope density, as other neutralizing HMAbs, suggesting that neutralization is epitope specific and not by binding to any surface epitope. The dose-dependent neutralizing activity of CBH-7, an HMAb to a domain C epitope in spatial proximity to domain A, and of CBH-5, a domain B HMAb to a more distant epitope, were tested in the presence and absence of each domain A HMAb. No enhancement or reduction in CBH-7 or CBH-5 neutralizing activity was observed, indicating that the potential induction of nonneutralizing antibodies should not be a central issue for HCV vaccine design. To assess whether domain A is involved in the structural changes as part of a pH-dependent virus envelope fusion process, changes in antibody binding patterns to normal pH and acid pH-treated HCVpp were measured. Antibody binding affinity of HMAbs to HCVpp was not affected by low pH. However, the B max values for low-pH-treated HCVpp with antibodies to domain A increased 46%, for domain C (CBH-7) they increased 23%, and for domain B (CBH-5) there was a decrease of 12%. Collectively, the organization and function of HCV E2 antigenic domains are roughly analogous to the large envelope glycoprotein E organizational structure for other flaviviruses with three distinct structural and functional domains.

On the propagation of the OH radical produced by Cu-amyloid beta peptide model complexes. Insight from molecular modelling

Metallomics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1765-1780
Author(s):  
Federica Arrigoni ◽  
Fabio Rizza ◽  
Renata Tisi ◽  
Luca De Gioia ◽  
Giuseppe Zampella ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Molecular Modelling ◽  
Amyloid Beta Peptide ◽  
Side Chains ◽  
Oh Radical ◽  
Ros Production ◽  
Aβ Peptide ◽  
Model Complexes ◽  
Beta Peptide ◽  
Amyloid Aβ

Alzheimer's disease involves an anomalous interaction of copper with the amyloid Aβ peptide, inducing ROS production. The propagation of the OH radical toward Aβ side chains is investigated by molecular modelling.

scholarly journals N-terminal engineering of amyloid-β-binding Affibody molecules yields improved chemical synthesis and higher binding affinity

2010 ◽  
Vol 19 (12) ◽  
pp. 2319-2329 ◽  
Author(s):  
Joel Lindgren ◽  
Anna Wahlström ◽  
Jens Danielsson ◽  
Natalia Markova ◽  
Caroline Ekblad ◽  
...  
Keyword(s):  
Chemical Synthesis ◽  
Binding Affinity ◽  
Amyloid Β ◽  
Affibody Molecules

scholarly journals Accumulation of Innate Amyloid Beta Peptide in Glioblastoma Tumors

2019 ◽  
Vol 20 (10) ◽  
pp. 2482 ◽  
Author(s):  
Lilia Y. Kucheryavykh ◽  
Jescelica Ortiz-Rivera ◽  
Yuriy V. Kucheryavykh ◽  
Astrid Zayas-Santiago ◽  
Amanda Diaz-Garcia ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Amyloid Beta ◽  
Glioma Cells ◽  
Amyloid Beta Peptide ◽  
Enzyme Linked Immunosorbent Assay ◽  
Aβ Peptide ◽  
Brain Areas ◽  
Aβ Peptides ◽  
Beta Peptide ◽  
Glioma Tumors

Immunostaining with specific antibodies has shown that innate amyloid beta (Aβ) is accumulated naturally in glioma tumors and nearby blood vessels in a mouse model of glioma. In immunofluorescence images, Aβ peptide coincides with glioma cells, and enzyme-linked immunosorbent assay (ELISA) have shown that Aβ peptide is enriched in the membrane protein fraction of tumor cells. ELISAs have also confirmed that the Aβ(1–40) peptide is enriched in glioma tumor areas relative to healthy brain areas. Thioflavin staining revealed that at least some amyloid is present in glioma tumors in aggregated forms. We may suggest that the presence of aggregated amyloid in glioma tumors together with the presence of Aβ immunofluorescence coinciding with glioma cells and the nearby vasculature imply that the source of Aβ peptides in glioma can be systemic Aβ from blood vessels, but this question remains unresolved and needs additional studies.

scholarly journals Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons

2013 ◽  
Vol 219 (5) ◽  
pp. 1527-1541 ◽  
Author(s):  
Saak V. Ovsepian ◽  
Inga Antyborzec ◽  
Valerie B. O’Leary ◽  
Laszlo Zaborszky ◽  
Jochen Herms ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Neurotrophin Receptor ◽  
Aβ Peptide ◽  
Basal Forebrain Cholinergic Neurons

scholarly journals Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

2021 ◽  
Author(s):  
Liang Sun ◽  
Hong-Jun Cho ◽  
Soumyo Sen ◽  
Andres S. Arango ◽  
Truc T. Huynh ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
5Xfad Mice ◽  
Soluble Aβ Oligomers

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers <i>in vivo</i>, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the <sup>64</sup>Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these <i>in vitro</i> and <i>in vivo</i> studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

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