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 Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment

2002 ◽  
Vol 366 (1) ◽  
pp. 343-351 ◽  
Author(s):  
Lars O. TJERNBERG ◽  
Agneta TJERNBERG ◽  
Niklas BARK ◽  
Yuan SHI ◽  
Bela P. RUZSICSKA ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Structural Features ◽  
Fibril Formation ◽  
Amyloid Β Peptide ◽  
Detailed Model ◽  
Aβ Fibrils ◽  
Β Sheet

The amyloid plaque, consisting of amyloid β-peptide (Aβ) fibrils surrounded by dystrophic neurites, is an invariable feature of Alzheimer's disease. The determination of the molecular structure of Aβ fibrils is a significant goal that may lead to the structure-based design of effective therapeutics for Alzheimer's disease. Technical challenges have thus far rendered this goal impossible. In the present study, we develop an alternative methodology. Rather than determining the structure directly, we design conformationally constrained peptides and demonstrate that only certain ‘bricks’ can aggregate into fibrils morphologically identical to Aβ fibrils. The designed peptides include variants of a decapeptide fragment of Aβ, previously shown to be one of the smallest peptides that (1) includes a pentapeptide sequence necessary for Aβ—Aβ binding and aggregation and (2) can form fibrils indistinguishable from those formed by full-length Aβ. The secondary structure of these bricks is monitored by CD spectroscopy, and electron microscopy is used to study the morphology of the aggregates formed. We then made various residue deletions and substitutions to determine which structural features are essential for fibril formation. From the constraints, statistical analysis of side-chain pair correlations in β-sheets and experimental data, we deduce a detailed model of the peptide strand alignment in fibrils formed by these bricks. Our results show that the constrained decapeptide dimers rapidly form an intramolecular, antiparallel β-sheet and polymerize into amyloid fibrils at low concentrations. We suggest that the formation of an exposed β-sheet (e.g. an Aβ dimer formed by interaction in the decapeptide region) could be a rate-limiting step in fibril formation. A theoretical framework that explains the results is presented in parallel with the data.

The p3 Peptide, a Naturally Occurring Fragment of the Amyloid-β Peptide (Aβ)Found in Alzheimer's Disease, Has a Greater Aggregation Propensity In Vitro Than Full-Length Aβ, But Does Not Bind Cu2+.

2000 ◽  
Vol 53 (4) ◽  
pp. 321 ◽  
Author(s):  
Feda Ali ◽  
Andrew J. Thompson ◽  
Colin J. Barrow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Sheet Structure ◽  
Β Sheet

Cerebellar preamyloid from both Down’s syndrome and Alzheimer’s disease contains the p3 fragment (Aβ 17–40/42) as a major amyloid-β peptide (Aβ) component. The p3 peptide was previously shown to form amyloid in vitro, but less readily than full-length Aβ. Here we show that the p3 peptide has a greater β-sheet-forming propensity than full-length Aβ. Using circular dichroism spectroscopy we determined that in aqueous solutions the p3 peptide forms β-sheet structure more readily than full-length Aβ. The p3 peptide also has a lower α-helical propensity than full-length Aβ in the structure-forming solvent trifluoroethanol. These results indicate that the lower amyloidogenicity of the p3 peptide is not related to an inability to form β-sheet structure. In this study we also show that, unlike full-length Aβ, the p3 peptide does not bind Cu2+ ions. This inability to bind copper ions may explain why the p3 peptide appears to play a lesser role in Down’s syndrome and Alzheimer’s disease related neurodegeneration than does full-length Aβ.

scholarly journals Endo-lysosomal Aβ concentration and pH enable formation of Aβ oligomers that potently induce Tau missorting

2020 ◽  
Author(s):  
Marie P. Schützmann ◽  
Filip Hasecke ◽  
Sarah Bachmann ◽  
Mara Zielinski ◽  
Sebastian Hänsch ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Oligomers ◽  
Lysosomal Ph ◽  
Amyloid Fibril Formation ◽  
Aβ Amyloid ◽  
Key Factor ◽  
Lysosomal System

AbstractAmyloid-β peptide (Aβ) forms metastable oligomers >50 kD, termed AβOs or protofibrils, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.

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

Structural origin of polymorphism of Alzheimer's amyloid β-fibrils

2012 ◽  
Vol 447 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Audrey Agopian ◽  
Zhefeng Guo
Keyword(s):  
Amyloid Fibrils ◽  
Spin Exchange ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Side Chain ◽  
Resonance Spectroscopy ◽  
Amyloid Β Peptide ◽  
Amyloid Proteins ◽  
Aβ Amyloid

Formation of senile plaques containing amyloid fibrils of Aβ (amyloid β-peptide) is a pathological hallmark of Alzheimer's disease. Unlike globular proteins, which fold into unique structures, the fibrils of Aβ and other amyloid proteins often contain multiple polymorphs. Polymorphism of amyloid fibrils leads to different toxicity in amyloid diseases and may be the basis for prion strains, but the structural origin for fibril polymorphism is still elusive. In the present study we investigate the structural origin of two major fibril polymorphs of Aβ40: an untwisted polymorph formed under agitated conditions and a twisted polymorph formed under quiescent conditions. Using electron paramagnetic resonance spectroscopy, we studied the inter-strand side-chain interactions at 14 spin-labelled positions in the Aβ40 sequence. The results of the present study show that the agitated fibrils have stronger inter-strand spin–spin interactions at most of the residue positions investigated. The two hydrophobic regions at residues 17–20 and 31–36 have the strongest interactions in agitated fibrils. Distance estimates on the basis of the spin exchange frequencies suggest that inter-strand distances at residues 17, 20, 32, 34 and 36 in agitated fibrils are approximately 0.2 Å (1 Å=0.1 nm) closer than in quiescent fibrils. We propose that the strength of inter-strand side-chain interactions determines the degree of β-sheet twist, which then leads to the different association patterns between different cross β-units and thus distinct fibril morphologies. Therefore the inter-strand side-chain interaction may be a structural origin for fibril polymorphism in Aβ and other amyloid proteins.

scholarly journals Monomeric amyloid β-peptide (1-42) significantly populates compact fibril-like conformations

2020 ◽  
Author(s):  
Bogdan Barz ◽  
Alexander K. Buell ◽  
Soumav Nath
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Random Coil ◽  
Amyloid Β Peptide ◽  
Secondary Nucleation ◽  
Fibril Structure ◽  
Amyloid Fibril Formation ◽  
Dynamics Simulations ◽  
The Individual ◽  
Structural Ensemble

AbstractThe aggregation of the amyloid β (Aβ) peptide is a major hallmark of Alzheimer’s disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units, and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. The structure of the Aβ monomer has been shown to be very dynamic and mostly disordered, both in experimental and in computational studies, similar to a random coil. This structural state of the monomer contrasts with the very stable and well defined structural core of the amyloid fibrils. An important question is whether the monomer can adopt transient fibril-like conformations in solution and what role such conformations might play in the aggregation process. Here we use enhanced and extensive molecular dynamics simulations to study the Aβ42 monomer structural flexibility with different force fields, water models and salt concentrations. We show that the monomer behaves as a random coil under different simulation conditions. Importantly, we find a conformation with the N-terminal region structured very similarly to that of recent experimentally determined fibril models. This is to the best of our knowledge the first monomeric structural ensemble to show such a similarity with the fibril structure.

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

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.

Glycation induces conformational changes in the amyloid-β peptide and enhances its aggregation propensity: molecular insights

2016 ◽  
Vol 18 (46) ◽  
pp. 31446-31458 ◽  
Author(s):  
Asis K. Jana ◽  
Kedar B. Batkulwar ◽  
Mahesh J. Kulkarni ◽  
Neelanjana Sengupta
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Advanced Glycation ◽  
Aggregation Propensity

Underlying molecular insights into the higher aggregation propensity of the advanced glycation modified Aβ (or AGE-Aβ) from synchronizedin vitroandin silicostudies.

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