Quantifying Amyloid β-Peptide (Aβ) Aggregation Using the Congo Red-Aβ (CR–Aβ) Spectrophotometric Assay

1999 ◽  
Vol 266 (1) ◽  
pp. 66-76 ◽  
Author(s):  
William E. Klunk ◽  
Robert F. Jacob ◽  
R.Preston Mason
Keyword(s):  
Congo Red ◽  
Amyloid Β ◽  
Spectrophotometric Assay ◽  
Amyloid Β Peptide ◽  
Aβ Aggregation

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 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.

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.

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

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.

scholarly journals A dopamine metabolite stabilizes neurotoxic amyloid-β oligomers

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Rodrigo Cataldi ◽  
Sean Chia ◽  
Katarina Pisani ◽  
Francesco S. Ruggeri ◽  
Catherine K. Xu ◽  
...  
Keyword(s):  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Cytosolic Calcium ◽  
Dopamine Metabolism ◽  
Amyloid Β Peptide ◽  
Human Neuroblastoma ◽  
Biochemical Processes ◽  
Aβ Aggregation ◽  
Pathogenic Agents ◽  
The Brain

AbstractAberrant soluble oligomers formed by the amyloid-β peptide (Aβ) are major pathogenic agents in the onset and progression of Alzheimer’s disease. A variety of biomolecules can influence the formation of these oligomers in the brain, although their mechanisms of action are still largely unknown. Here, we studied the effects on Aβ aggregation of DOPAL, a reactive catecholaldehyde intermediate of dopamine metabolism. We found that DOPAL is able to stabilize Aβ oligomeric species, including dimers and trimers, that exert toxic effects on human neuroblastoma cells, in particular increasing cytosolic calcium levels and promoting the generation of reactive oxygen species. These results reveal an interplay between Aβ aggregation and key biochemical processes regulating cellular homeostasis in the brain.

Inhibitory Mechanism of An Anticancer Drug, Bexarotene Against Amyloid β Peptide Aggregation: Repurposing Via Neuroinformatics Approach

2019 ◽  
Vol 25 (27) ◽  
pp. 2989-2995
Author(s):  
Nousheen Bibi ◽  
Syed M.D. Rizvi ◽  
Abida Batool ◽  
Mohammad A. Kamal
Keyword(s):  
Anticancer Drug ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Drug Repurposing ◽  
Drug Candidate ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Aβ Peptide ◽  
Aβ Aggregation ◽  
Bace 1

Background: Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame Amyloid fibrils, which is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress Aβ-peptide aggregation. However, the exact mechanistic aspect of suppression of Aβ-peptide accumulation has not yet been completely revealed. Methods: In the present study, we have attempted to decipher the mechanistic aspects of the anti-aggregation potential of bexarotene by using the computational biology approach. Results: We have observed the effect of ‘Aβ-bexarotene’ interaction on the aggregation ability of the Aβ-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). A deep structural analysis of Aβ upon binding with bexarotene revealed critical binding sites and structural twists involved in Aβ aggregation. It is evident from the present that bexarotene could significantly restrain the process of primary nucleation of Aβ. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene. Conclusion: Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce Aβ- peptide aggregation by applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entities against AD.

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