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 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.

scholarly journals Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication

2017 ◽  
Vol 114 (25) ◽  
pp. 6444-6449 ◽  
Author(s):  
Anna Munke ◽  
Jonas Persson ◽  
Tanja Weiffert ◽  
Erwin De Genst ◽  
Georg Meisl ◽  
...  
Keyword(s):  
Phage Display ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Nucleation Process ◽  
Single Chain ◽  
Secondary Nucleation ◽  
Single Chain Antibody ◽  
Phage Display Libraries ◽  
Selection Of

The aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is a defining characteristic of Alzheimer’s disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Aβ (Aβ42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Aβ42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection of scFvs with high affinity for Aβ42 fibrils after removal of scFvs that bind Aβ42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Aβ42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in Aβ42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril-dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer’s and related neurodegenerative diseases.

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

2021 ◽  
Vol 12 (1) ◽  
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 kDa, termed AβOs, 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.

scholarly journals Remarked Suppression of Aβ 42 Protomer-Protomer Dissociation Reaction Elucidated by Molecular Dynamics Simulation

2021 ◽  
Author(s):  
Ikuo Kurisaki ◽  
Shigenori Tanaka
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Amyloid Fibrils ◽  
Protein Complexes ◽  
Amyloid Β ◽  
Dynamics Simulation ◽  
Physicochemical Condition ◽  
Technical Limitation ◽  
Amyloid Fibril Formation ◽  
Dynamics Simulations

Multimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half-century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril-like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid-β (1-42) (Aβ ). Seven different dimeric forms of oligomeric Aβ fibril-like aggregate in aqueous solution, ranging from tetramer to decamer, were considered. We found additive effects of the size of these fibril-like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer-protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the Aβ protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril-like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered.

Destabilization of Alzheimer’s Aβ42 protofibrils with acyclovir, carmustine, curcumin, and tetracycline: Insights from molecular dynamics simulations

2021 ◽  
Author(s):  
Ishrat Jahan ◽  
Shahid M Nayeem
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Neurodegenerative Diseases ◽  
Molecular Dynamics Simulations ◽  
Amyloid Β ◽  
Neural Tissue ◽  
Amyloid Β Peptide ◽  
Characteristic Symptom ◽  
Dynamics Simulations

One of the most common dementia among neurodegenerative diseases is Alzheimer’s disease (AD). The characteristic symptom of AD is the deposition and aggregation of amyloid-β-peptide in the neural tissue. A...

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 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.

Binding modes of thioflavin T and Congo red to the fibril structure of amyloid-β(1–42)

2020 ◽  
Vol 56 (55) ◽  
pp. 7589-7592 ◽  
Author(s):  
Benedikt Frieg ◽  
Lothar Gremer ◽  
Henrike Heise ◽  
Dieter Willbold ◽  
Holger Gohlke
Keyword(s):  
Congo Red ◽  
Fluorescent Dyes ◽  
Binding Free Energy ◽  
Amyloid Β ◽  
Free Energy Calculations ◽  
Thioflavin T ◽  
Binding Modes ◽  
Fibril Structure ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

Binding modes for the amyloid-β(1–42) fibril fluorescent dyes thioflavin T and Congo red were predicted by molecular dynamics simulations and binding free energy calculations.

Sign in / Sign up

Export Citation Format

Share Document