scholarly journals Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sahar Andarzi Gargari ◽  
Abolfazl Barzegar
Keyword(s):  
Amyloid Β ◽  
Atomic Scale ◽  
Amyloid Β Peptide ◽  
Salt Bridges ◽  
Linear Interaction ◽  
Computational Evaluation ◽  
High Interaction ◽  
Aβ Aggregation ◽  
Aggregation Inhibition ◽  
Β Sheets

Abstract Structural studies of the aggregation inhibition of the amyloid-β peptide (Aβ) by different natural compounds are of the utmost importance due to their great potential as neuroprotective and therapeutic agents for Alzheimer’s disease. We provided the simulation of molecular dynamics for two different states of Aβ42, including “monomeric aggregation-prone state (APS)” and “U-shaped pentamers of amyloidogenic protofilament intermediates” in the absence and presence of polyphenolic flavonoids (Flvs, myricetin and morin) in order to verify the possible mechanism of Flvs fibrillogenesis suppression. Data showed that Flvs directly bind into Aβ42 species in both states of “monomeric APS β-sheets” and “pentameric amyloidogenic intermediates”. Binding of Flvs with amyloidogenic protofilament intermediates caused the attenuation of some inter-chains H-bonds, salt bridges, van der Waals and interpeptide interaction energies without interfering with their secondary β-sheets. Therefore, Flvs redirect oligomeric amyloidogenic intermediates into unstructured aggregates by significant disruption of the "steric zipper" motif of fibrils—pairs of self-complementary β-sheets—without changing the amount of β-sheets. It is while Flvs completely destruct the disadvantageous secondary β-sheets of monomeric APS conformers by converting them into coil/helix structures. It means that Flvs suppress the fibrillogenesis process of the monomeric APS structures by converting their β-sheets into proper soluble coil/helices structures. The different actions of Flvs in contact with two different states of Aβ conformers are related to high interaction tendency of Flvs with additional H-bonds for monomeric APS β-sheet, rather than oligomeric protofilaments. Linear interaction energy (LIE) analysis confirmed the strong binding of monomeric Aβ-Flvs with more negative ∆Gbinding, rather than oligomeric Aβ-Flvs system. Therefore, atomic scale computational evaluation of Flvs actions demonstrated different dual functions of Flvs, concluded from the application of two different monomeric and pentameric Aβ42 systems. The distinct dual functions of Flvs are proposed as suppressing the aggregation by converting β-sheets of monomeric APS to proper soluble structures and disrupting the "steric zipper" fibril motifs of oligomeric intermediate by converting on-pathway into off-pathway. Taken together, our data propose that Flvs exert dual and more effective functions against monomeric APS (fibrillogenesis suppression) and remodel the Aβ aggregation pathway (fibril destabilization).

scholarly journals Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates

2017 ◽  
Vol 114 (30) ◽  
pp. 8005-8010 ◽  
Author(s):  
Sean Chia ◽  
Patrick Flagmeier ◽  
Johnny Habchi ◽  
Veronica Lattanzi ◽  
Sara Linse ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Heterogeneous Nucleation ◽  
Amyloid Β ◽  
Catalytic Cycle ◽  
Amyloid Β Peptide ◽  
Complex Interplay ◽  
Parkinson’S Diseases ◽  
Aβ Aggregation ◽  
Aβ Fibrils

The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.

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 Mechanism of amyloid protein aggregation and the role of inhibitors

2019 ◽  
Vol 91 (2) ◽  
pp. 211-229 ◽  
Author(s):  
Sara Linse
Keyword(s):  
Total Concentration ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aggregation Process ◽  
Secondary Nucleation ◽  
Toxic Species ◽  
Primary Nucleation ◽  
Effective Inhibition ◽  
Aβ Aggregation

Abstract Inhibition of amyloid β peptide (Aβ) aggregation is an important goal due to the connection of this process with Alzheimer’s disease. Traditionally, inhibitors were developed with an aim to retard the overall macroscopic aggregation. However, recent advances imply that approaches based on mechanistic insights may be more powerful. In such approaches, the microscopic steps underlying the aggregation process are identified, and it is established which of these step(s) lead to neurotoxicity. Inhibitors are then derived to specifically target steps involved in toxicity. The Aβ aggregation process is composed of at minimum three microscopic steps: primary nucleation of monomers only, secondary nucleation of monomers on fibril surface, and elongation of fibrils by monomer addition. The vast majority of toxic species are generated from the secondary nucleation process: this may be a key process to inhibit in order to limit toxicity. Inhibition of primary nucleation, which delays the emergence of toxic species without affecting their total concentration, may also be effective. Inhibition of elongation may instead increase the toxicity over time. Here we briefly review findings regarding secondary nucleation of Aβ, its dominance over primary nucleation, and attempts to derive inhibitors that specifically target secondary nucleation with an aim to limit toxicity.

scholarly journals Pyroglutamylated Amyloid-β Peptide Reverses Cross β-Sheets by a Prion-Like Mechanism

2014 ◽  
Vol 118 (21) ◽  
pp. 5637-5643 ◽  
Author(s):  
Jason O. Matos ◽  
Greg Goldblatt ◽  
Jaekyun Jeon ◽  
Bo Chen ◽  
Suren A. Tatulian
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Β Sheets

The inhibitory mechanism of a fullerene derivative against amyloid-β peptide aggregation: an atomistic simulation study

2016 ◽  
Vol 18 (18) ◽  
pp. 12582-12591 ◽  
Author(s):  
Yunxiang Sun ◽  
Zhenyu Qian ◽  
Guanghong Wei
Keyword(s):  
Simulation Study ◽  
Atomistic Simulation ◽  
Amyloid Β ◽  
Fullerene Derivative ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Inhibitory Mechanism ◽  
Aβ Oligomers ◽  
Β Sheets

Fullerene inhibits the formation of inter-peptide β-sheets and β-hairpin motifs of toxic Aβ oligomers by binding to F4, Y10, L17–A21 and I31–V40 residues.

Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila

2016 ◽  
Vol 473 (20) ◽  
pp. 3683-3704 ◽  
Author(s):  
Helen Poska ◽  
Martin Haslbeck ◽  
Firoz Roshan Kurudenkandy ◽  
Erik Hermansson ◽  
Gefei Chen ◽  
...  
Keyword(s):  
Hippocampal Slices ◽  
Amyloid Β ◽  
Mushroom Bodies ◽  
Amyloid Β Peptide ◽  
Specific Expression ◽  
Efficient Inhibitor ◽  
Transgenic Expression ◽  
Aβ Aggregation

Formation of fibrils of the amyloid-β peptide (Aβ) is suggested to play a central role in neurodegeneration in Alzheimer's disease (AD), for which no effective treatment exists. The BRICHOS domain is a part of several disease-related proproteins, the most studied ones being Bri2 associated with familial dementia and prosurfactant protein C (proSP-C) associated with lung amyloid. BRICHOS from proSP-C has been found to be an efficient inhibitor of Aβ aggregation and toxicity, but its lung-specific expression makes it unsuited to target in AD. Bri2 is expressed in the brain, affects processing of Aβ precursor protein, and increased levels of Bri2 are found in AD brain, but the specific role of its BRICHOS domain has not been studied in vivo. Here, we find that transgenic expression of the Bri2 BRICHOS domain in the Drosophila central nervous system (CNS) or eyes efficiently inhibits Aβ42 toxicity. In the presence of Bri2 BRICHOS, Aβ42 is diffusely distributed throughout the mushroom bodies, a brain region involved in learning and memory, whereas Aβ42 expressed alone or together with proSP-C BRICHOS forms punctuate deposits outside the mushroom bodies. Recombinant Bri2 BRICHOS domain efficiently prevents Aβ42-induced reduction in γ-oscillations in hippocampal slices. Finally, Bri2 BRICHOS inhibits several steps in the Aβ42 fibrillation pathway and prevents aggregation of heat-denatured proteins, indicating that it is a more versatile chaperone than proSP-C BRICHOS. These findings suggest that Bri2 BRICHOS can be a physiologically relevant chaperone for Aβ in the CNS and needs to be further investigated for its potential in AD treatment.

A Cationic Gallium Phthalocyanine Inhibits Amyloid β Peptide Fibril Formation

2020 ◽  
Vol 17 (7) ◽  
pp. 589-600
Author(s):  
Shatera Tabassum ◽  
Abdullah Md. Sheikh ◽  
Shozo Yano ◽  
Takahisa Ikeue ◽  
Shingo Mitaki ◽  
...  
Keyword(s):  
Near Infrared ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Fibril Formation ◽  
Lag Phase ◽  
Slice Culture ◽  
Amyloid Β Peptide ◽  
Protective Effects ◽  
Aβ Aggregation

Background: Amyloid β (Aβ) peptide deposition is considered as the main cause of Alzheimer’s disease (AD). Previously, we have shown that a Zn containing neutral phthalocyanine (Zn-Pc) inhibits Aβ fibril formation. Objective: The objective of this study is to investigate the effects of a cationic gallium containing Pc (GaCl-Pc) on Aβ fibril formation process. Methods and Results: Aβ fibril formation was induced by incubating synthetic Aβ peptides in a fibril forming buffer, and the amount of fibril was evaluated by ThT fluorescence assay. GaCl-Pc dosedependently inhibited both Aβ1-40 and Aβ1-42 fibril formation. It mainly inhibited the elongation phase of Aβ1-42 fibril formation kinetics, but not the lag phase. Western blotting results showed that it did not inhibit its oligomerization process, rather increased it. Additionally, GaCl-Pc destabilized preformed Aβ1- 42 fibrils dose-dependently in vitro condition, and decreased Aβ levels in the brain slice culture of APP transgenic AD model mice (J20 strain). Near-infrared scanning results showed that GaCl-Pc had the ability to bind to Aβ1-42. MTT assay demonstrated that GaCl-Pc did not have toxicity towards a neuronal cell line (A1) in culture rather, showed protective effects on Aβ-induced toxicity. Moreover, it dosedependently decreased Aβ-induced reactive oxygen species levels in A1 culture. Conclusion: Thus, our result demonstrated that GaCl-Pc decreased Aβ aggregation and destabilized the preformed fibrils. Since cationic molecules show a better ability to cross the blood-brain barrier, cationic GaCl-Pc could be important for the therapy of AD.

scholarly journals Aggregation Mechanism of Alzheimer’s Amyloid β-Peptide Mediated by α-Strand/α-Sheet Structure

2020 ◽  
Vol 21 (3) ◽  
pp. 1094 ◽  
Author(s):  
Anand Balupuri ◽  
Kwang-Eun Choi ◽  
Nam Sook Kang
Keyword(s):  
Neuronal Damage ◽  
Experimental Studies ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aggregation Mechanism ◽  
Toxic Species ◽  
Sheet Structure ◽  
Aβ Aggregation ◽  
Dynamics Simulations ◽  
Structural Insights

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and a widespread form of dementia. Aggregated forms of the amyloid β-peptide (Aβ) are identified as a toxic species responsible for neuronal damage in AD. Extensive research has been conducted to reveal the aggregation mechanism of Aβ. However, the structure of pathological aggregates and the mechanism of aggregation are not well understood. Recently, experimental studies have confirmed that the α-sheet structure in Aβ drives aggregation and toxicity in AD. However, how the α-sheet structure is formed in Aβ and how it contributes to Aβ aggregation remains elusive. In the present study, molecular dynamics simulations suggest that Aβ adopts the α-strand conformation by peptide-plane flipping. Multiple α-strands interact through hydrogen bonding to form α-sheets. This structure acts as a nucleus that initiates and promotes aggregation and fibrillation of Aβ. Our findings are supported by previous experimental as well as theoretical studies. This study provides valuable structural insights for the design of anti-AD drugs exploiting the α-strand/α-sheet structure.

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