scholarly journals The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers

Oncotarget ◽  
2017 ◽  
Vol 8 (25) ◽  
pp. 41154-41165 ◽  
Author(s):  
Victòria Valls-Comamala ◽  
Biuse Guivernau ◽  
Jaume Bonet ◽  
Marta Puig ◽  
Alex Perálvarez-Marín ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Peptide Folding ◽  
Antigen Binding ◽  
Amyloid Β Peptide ◽  
Β Sheet

Copper selectively triggers β-sheet assembly of an N-terminally truncated amyloid β-peptide beginning with Glu3

2004 ◽  
Vol 98 (1) ◽  
pp. 10-14 ◽  
Author(s):  
Takashi Miura ◽  
Sayoko Mitani ◽  
Chiho Takanashi ◽  
Nobuhiro Mochizuki
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Β Sheet

scholarly journals Out-of-register parallel β-sheets and antiparallel β-sheets coexist in 150 kDa oligomers formed by Aβ(1-42)

2020 ◽  
Author(s):  
Yuan Gao ◽  
Cong Guo ◽  
Jens O. Watzlawik ◽  
Elizabeth J. Lee ◽  
Danting Huang ◽  
...  
Keyword(s):  
Solid State Nmr ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Dipolar Recoupling ◽  
Negative Results ◽  
Assembly Pathway ◽  
Fibril Structure ◽  
Proposed Model ◽  
Β Sheets ◽  
Β Sheet

AbstractWe present solid-state NMR measurements of β-strand secondary structure and inter-strand organization within a 150 kDa oligomeric aggregate of the 42-residue variant of the Alzheimer’s amyloid-β peptide (Aβ(1-42)). This oligomer is characterized by a structure that cannot be explained by any previously proposed model for aggregated Aβ. We build upon our previous report of a β-strand spanned by residues 30-42, which arranges into an antiparallel β-sheet. New results presented here indicate that there is a second β-strand formed by residues 11-24. We show negative results for NMR experiments designed to reveal antiparallel β-sheets formed by this β-strand. Remarkably, we show that this strand is organized into a parallel β-sheet despite the co-existence of an antiparallel β-sheet in the same structure. In addition, the in-register parallel β-sheet commonly observed for amyloid fibril structure does not apply to residues 11-24 in the 150 kDa oligomer. Rather, we present evidence for an inter-strand registry shift of 3 residues that alternates in direction between adjacent molecules along the β-sheet. We corroborated this unexpected scheme for β-strand organization using multiple 2-dimensional NMR and 13C-13C dipolar recoupling experiments. Our findings indicate a previously unknown assembly pathway and inspire a suggestion as to why this aggregate does not grow to larger sizes.

scholarly journals Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2129 ◽  
Author(s):  
Tao Zhang ◽  
Jennifer Loschwitz ◽  
Birgit Strodel ◽  
Luitgard Nagel-Steger ◽  
Dieter Willbold
Keyword(s):  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Amyloid Β Peptide ◽  
Amino Acid Residues ◽  
Ligand Interaction ◽  
Drug Candidates ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
First Time ◽  
Β Sheet

Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs.

scholarly journals Study of Amyloid β-Peptide (Aβ12-28-Cys) Interactions with Congo Red and β-Sheet Breaker Peptides Using Electrochemical Impedance Spectroscopy

Langmuir ◽  
2012 ◽  
Vol 28 (15) ◽  
pp. 6377-6385 ◽  
Author(s):  
Raheleh Partovi-Nia ◽  
Samaneh Beheshti ◽  
Ziqiang Qin ◽  
Himadri S. Mandal ◽  
Yi-Tao Long ◽  
...  
Keyword(s):  
Electrochemical Impedance Spectroscopy ◽  
Impedance Spectroscopy ◽  
Congo Red ◽  
Electrochemical Impedance ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Β Sheet

Aggregation and neurotoxicity of α-synuclein and related peptides

2002 ◽  
Vol 30 (4) ◽  
pp. 559-565 ◽  
Author(s):  
O. M. A. EI-Agnaf ◽  
G. B. Irvine
Keyword(s):  
Electron Microscopy ◽  
Antioxidant Properties ◽  
Amyloid Β ◽  
Cd Spectroscopy ◽  
Amyloid Β Peptide ◽  
Peptide Component ◽  
Mutant Forms ◽  
Β Sheet ◽  
Early Onset Parkinson’S Disease ◽  
Apoptotic Mechanism

Fibrillar deposits of α-synuclein occur in several neurodegenerative diseases. Two mutant forms of α-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-β peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of α-synuclein and NAC change conformation to β-sheet, detectable by CD spectroscopy, and form oligomers that deposit as amyloid-like fibrils, detectable by electron microscopy. These aged peptides are also neurotoxic. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified. NAC(8–18) is the smallest fragment that aggregates, as indicated by the concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. Fragments NAC(8–18) and NAC(8–16) are toxic, whereas NAC(12–18), NAC(9–16) and NAC(8–15) are not. Hence residues 8–16 of NAC comprise the region crucial for toxicity. Toxicity induced by α-synuclein, NAC and NAC(1–18) oligomers occurs via an apoptotic mechanism, possibly initiated by oxidative damage, since these peptides liberate hydroxyl radicals in the presence of iron. Molecules with anti-aggregational and/or antioxidant properties may therefore be potential therapeutic agents.

Inhibition of Alzheimer's amyloid-β peptide aggregation and its disruption by a conformationally restricted α/β hybrid peptide

2015 ◽  
Vol 51 (12) ◽  
pp. 2245-2248 ◽  
Author(s):  
Ashim Paul ◽  
Krishna Chaitanya Nadimpally ◽  
Tanmay Mondal ◽  
Kishore Thalluri ◽  
Bhubaneswar Mandal
Keyword(s):  
Anthranilic Acid ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Hybrid Peptide ◽  
Conformationally Restricted ◽  
Β Sheet

A novel class of anthranilic acid containing a conformationally restricted β-sheet breaker α/β-hybrid peptide efficiently disrupts preformed fibrillar aggregates of Aβ1–40in vitro.

scholarly journals Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

2021 ◽  
Vol 118 (39) ◽  
pp. e2106210118
Author(s):  
Hebah Fatafta ◽  
Mohammed Khaled ◽  
Michael C. Owen ◽  
Abdallah Sayyed-Ahmad ◽  
Birgit Strodel
Keyword(s):  
Aqueous Phase ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Random Coil ◽  
Neuronal Membrane ◽  
Amyloid Β Peptide ◽  
Main Site ◽  
Neuronal Membranes ◽  
Β Sheet

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-β peptides in Alzheimer’s disease. To gain a detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-β (Aβ)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to β-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aβ-mediated toxicity.

scholarly journals Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

2021 ◽  
Author(s):  
Hebah Fatafta ◽  
Mohammed Khaled ◽  
Abdallah Sayyed-Ahmad ◽  
Birgit Strodel
Keyword(s):  
Aqueous Phase ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Md Simulations ◽  
Random Coil ◽  
Neuronal Membrane ◽  
Amyloid Β Peptide ◽  
Neuronal Membranes ◽  
Amyloid Oligomers ◽  
Β Sheet

The aggregation of amyloid β-peptides into neurotoxic oligomers is a key feature in the development of Alzheimer's disease. Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity. To gain a detailed understanding of the mutual effects of amyloid-β oligomers and the neuronal membrane, we carried out a total of 12 μs all-atom molecular dynamics (MD) simulations of the dimerization of the full-length Aβ42 peptide in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The conformational changes of Aβ42 resulting from its dimerization and interactions with the neuronal membrane are compared to those occurring upon its dimerization in the aqueous phase, which is also tested by 12 μs of MD simulations. We find that the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. Aβ42 dimerization in solution, on the other hand, is characterized by a random coil to β-sheet transition that seems to be on-pathway to amyloid aggregation. As the neurotoxic activity of amyloid oligomers increases with oligomer order, the results suggest that GM1 is neuroprotective against Aβ-mediated toxicity by inhibiting the formation of ordered amyloid oligomers.

scholarly journals Far-Off Resonance: Multiwavelength Raman Spectroscopy Probing Amide Bands of Amyloid-β-(37–42) Peptide

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3556
Author(s):  
Martynas Talaikis ◽  
Simona Strazdaitė ◽  
Mantas Žiaunys ◽  
Gediminas Niaura
Keyword(s):  
Raman Spectroscopy ◽  
Conformational Changes ◽  
Relative Intensity ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Intensity Increase ◽  
Amyloid Β Peptide ◽  
Peptide Backbone ◽  
Sheet Structure ◽  
Β Sheet

Several neurodegenerative diseases, like Alzheimer’s and Parkinson’s are linked with protein aggregation into amyloid fibrils. Conformational changes of native protein into the β-sheet structure are associated with a significant change in the vibrational spectrum. This is especially true for amide bands which are inherently sensitive to the secondary structure of a protein. Raman amide bands are greatly intensified under resonance conditions, in the UV spectral range, allowing for the selective probing of the peptide backbone. In this work, we examine parallel β-sheet forming GGVVIA, the C-terminus segment of amyloid-β peptide, using UV–Vis, FTIR, and multiwavelength Raman spectroscopy. We find that amide bands are enhanced far from the expected UV range, i.e., at 442 nm. A reasonable two-fold relative intensity increase is observed for amide II mode (normalized according to the δCH2/δCH3 vibration) while comparing 442 and 633 nm excitations; an increase in relative intensity of other amide bands was also visible. The observed relative intensification of amide II, amide S, and amide III modes in the Raman spectrum recorded at 442 nm comparing with longer wavelength (633/785/830 nm) excited spectra allows unambiguous identification of amide bands in the complex Raman spectra of peptides and proteins containing the β-sheet structure.

scholarly journals α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

2019 ◽  
Vol 116 (18) ◽  
pp. 8895-8900 ◽  
Author(s):  
Dylan Shea ◽  
Cheng-Chieh Hsu ◽  
Timothy M. Bi ◽  
Natasha Paranjapye ◽  
Matthew Carter Childers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Secondary Structure ◽  
De Novo ◽  
Specific Binding ◽  
Amyloid Β ◽  
Plaque Burden ◽  
Lag Phase ◽  
Amyloid Β Peptide ◽  
Β Sheet

Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

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