scholarly journals Borrelidin from Saltern-Derived Halophilic Nocardiopsis sp. Dissociates Amyloid-β and Tau Fibrils

2020 ◽  
pp. 1-7
Author(s):  
Jisu Shin ◽  
Seung-Hoon Yang ◽  
Young Eun Du ◽  
Keunwan Park ◽  
DaWon Kim ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Thioflavin T ◽  
Drug Candidate ◽  
Ht22 Cells ◽  
Aβ Aggregation ◽  
Actinomycete Strain ◽  
Direct Dissociation ◽  
Aβ Fibrils ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-β (Aβ) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aβ or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aβ and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. Objective: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aβ and tau aggregates through in vitro assessments. Methods: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aβ fibrils. Then, anti-cytotoxic, anti-Aβ, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. Results: When HT22 cells were exposed to Aβ aggregates, the treatment of borrelidins alleviates the Aβ-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aβ aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aβ aggregates but also directly regulates tau aggregation. Conclusion: Borrelidin dissociates insoluble Aβ and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aβ or anti-tau immunotherapy for clearance of both aggregates.

scholarly journals Blood-Brain Barrier Permeable 2-Phenylbenzothiazolyl Iridi-um Complexes as Inhibitors and Probes of Aβ Aggregation

2021 ◽  
Author(s):  
Yiran Huang ◽  
Hanah Na ◽  
Liang Sun ◽  
Karna Terpstra ◽  
Kai Gui ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Day Treatment ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Aβ Aggregation ◽  
D Values ◽  
Aβ Fibrils

The aggregation of amyloid β (Aβ) peptides is a significant hallmark of Alzheimer’s Disease (AD) and the inhibition and detection of Aβ aggregates are important for the treatment and diagnosis of AD. Herein, a series of benzothiazole-based luminescent Ir(III) complexes <b>HN-1</b> to <b>HN-8</b> were reported, which exhibit appreciable Aβ aggregation inhibition ability <i>in vitro</i> and in living cells. In addition, they are capable of inducing a fluorescence turn-on effect when binding to Aβ fibrils and oligomers. Most importantly, compared to previously reported cationic metal complexes, the neutral Ir complexes reported here show optimal Log D values, which suggest these compounds should have enhanced blood brain barrier (BBB) permeability. Most importantly, <i>in vivo</i> studies show that the neutral Ir complexes <b>HN-2</b>, <b>HN-3</b>, and <b>HN-8</b> successfully penetrate the BBB and stain amyloid plaques in AD mice brains after a 10-day treatment via i.p. injection, which is unprecedented for Ir(III) complexes, and thus can be used as lead compounds for AD therapeutics development.

scholarly journals Blood-Brain Barrier Permeable 2-Phenylbenzothiazolyl Iridi-um Complexes as Inhibitors and Probes of Aβ Aggregation

2021 ◽  
Author(s):  
Yiran Huang ◽  
Hanah Na ◽  
Liang Sun ◽  
Karna Terpstra ◽  
Kai Gui ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Day Treatment ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Aβ Aggregation ◽  
D Values ◽  
Aβ Fibrils

The aggregation of amyloid β (Aβ) peptides is a significant hallmark of Alzheimer’s Disease (AD) and the inhibition and detection of Aβ aggregates are important for the treatment and diagnosis of AD. Herein, a series of benzothiazole-based luminescent Ir(III) complexes <b>HN-1</b> to <b>HN-8</b> were reported, which exhibit appreciable Aβ aggregation inhibition ability <i>in vitro</i> and in living cells. In addition, they are capable of inducing a fluorescence turn-on effect when binding to Aβ fibrils and oligomers. Most importantly, compared to previously reported cationic metal complexes, the neutral Ir complexes reported here show optimal Log D values, which suggest these compounds should have enhanced blood brain barrier (BBB) permeability. Most importantly, <i>in vivo</i> studies show that the neutral Ir complexes <b>HN-2</b>, <b>HN-3</b>, and <b>HN-8</b> successfully penetrate the BBB and stain amyloid plaques in AD mice brains after a 10-day treatment via i.p. injection, which is unprecedented for Ir(III) complexes, and thus can be used as lead compounds for AD therapeutics development.

scholarly journals Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 924
Author(s):  
Nima Sasanian ◽  
David Bernson ◽  
Istvan Horvath ◽  
Pernilla Wittung-Stafshede ◽  
Elin K. Esbjörner
Keyword(s):  
Amyloid Fibrils ◽  
Copper Ions ◽  
Copper Ion ◽  
Amyloid Β ◽  
State Dependence ◽  
Theoretical Approaches ◽  
Aβ Aggregation ◽  
Ion Effects ◽  
Aβ Fibrils

Plaque deposits composed of amyloid-β (Aβ) fibrils are pathological hallmarks of Alzheimer’s disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with Aβ peptides in patients’ plaques, the molecular effects of copper ion interactions and redox-state dependence on Aβ aggregation remain elusive. By combining biophysical and theoretical approaches, we here show that Cu2+ (oxidized) and Cu+ (reduced) ions have opposite effects on the assembly kinetics of recombinant Aβ(1-42) into amyloid fibrils in vitro. Cu2+ inhibits both the unseeded and seeded aggregation of Aβ(1-42) at pH 8.0. Using mathematical models to fit the kinetic data, we find that Cu2+ prevents fibril elongation. The Cu2+-mediated inhibition of Aβ aggregation shows the largest effect around pH 6.0 but is lost at pH 5.0, which corresponds to the pH in lysosomes. In contrast to Cu2+, Cu+ ion binding mildly catalyzes the Aβ(1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu+-bridged Aβ(1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on Aβ(1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

2021 ◽  
Vol 22 (3) ◽  
pp. 1225
Author(s):  
Ziao Fu ◽  
William E. Van Nostrand ◽  
Steven O. Smith
Keyword(s):  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Aβ Oligomers ◽  
Dominant Component ◽  
Fibril Structure ◽  
Predominant Component ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Soluble Aβ Oligomers ◽  
Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

scholarly journals Aβ42 fibril formation from predominantly oligomeric samples suggests a link between oligomer heterogeneity and fibril polymorphism

2019 ◽  
Vol 6 (7) ◽  
pp. 190179 ◽  
Author(s):  
Christine Xue ◽  
Joyce Tran ◽  
Hongsu Wang ◽  
Giovanna Park ◽  
Frederick Hsu ◽  
...  
Keyword(s):  
Growth Rate ◽  
Green Tea ◽  
Epigallocatechin Gallate ◽  
Amyloid Β ◽  
Lag Time ◽  
Aβ Oligomers ◽  
Wide Range ◽  
Aβ Aggregation

Amyloid-β (Aβ) oligomers play a central role in the pathogenesis of Alzheimer's disease. Oligomers of different sizes, morphology and structures have been reported in both in vivo and in vitro studies, but there is a general lack of understanding about where to place these oligomers in the overall process of Aβ aggregation and fibrillization. Here, we show that Aβ42 spontaneously forms oligomers with a wide range of sizes in the same sample. These Aβ42 samples contain predominantly oligomers, and they quickly form fibrils upon incubation at 37°C. When fractionated using ultrafiltration filters, the samples enriched with smaller oligomers form fibrils at a faster rate than the samples enriched with larger oligomers, with both a shorter lag time and faster fibril growth rate. This observation is independent of Aβ42 batches and hexafluoroisopropanol treatment. Furthermore, the fibrils formed by the samples enriched with larger oligomers are more readily solubilized by epigallocatechin gallate, a main catechin component of green tea. These results suggest that the fibrils formed by larger oligomers may adopt a different structure from fibrils formed by smaller oligomers, pointing to a link between oligomer heterogeneity and fibril polymorphism.

scholarly journals The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

2020 ◽  
Vol 21 (3) ◽  
pp. 1066
Author(s):  
Roberta Corti ◽  
Alysia Cox ◽  
Valeria Cassina ◽  
Luca Nardo ◽  
Domenico Salerno ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Force Microscopy ◽  
Atomic Force ◽  
Nanoparticle Surface ◽  
Afm Imaging ◽  
Aggregation Processes ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Binding Sequence ◽  
The Brain

The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit Aβ aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling Aβ aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed Aβ fibrils or to hinder the Aβ aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling Aβ aggregation processes.

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 Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

2021 ◽  
Author(s):  
Elina Berntsson ◽  
Suman Paul ◽  
Faraz Vosough ◽  
Sabrina B. Sholts ◽  
Jüri Jarvet ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Underlying Mechanism ◽  
Aβ Peptides ◽  
Beneficial Effects ◽  
Incurable Disease ◽  
Age Related ◽  
Aβ Aggregation ◽  
In Vitro Interactions

Alzheimer’s disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has showed promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aβ peptides and modulate their aggregation and toxicity. The interactions between Aβ peptides and Li+ ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between Aβ peptides and Li+ ions. We show that Li+ ions display weak and non-specific interactions with Aβ peptides, and have minor effects on Aβ aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aβ peptides and Li+ ions.

scholarly journals Nanomedicine Against Aβ Aggregation by β–Sheet Breaker Peptide Delivery: In Vitro Evidence

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 572 ◽  
Author(s):  
Pederzoli ◽  
Ruozi ◽  
Duskey ◽  
Hagmeyer ◽  
Sauer ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Polymeric Nanoparticles ◽  
Therapeutic Option ◽  
Amyloid Β ◽  
Peptide Delivery ◽  
Cellular Toxicity ◽  
Free Peptide ◽  
Aβ Aggregation ◽  
Β Sheet

The accumulation of amyloid β (Aβ) triggers a cascade of toxic events in Alzheimer’s disease (AD). The KLVFF peptide can interfere with Aβ aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood–brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in biodistribution. We produced new engineered polymeric nanoparticles (NPs), and we evaluated the cellular toxicity of these NPs and validated that KVLFF peptides released by NPs show the same promising effects on AD pathology. Our results revealed the successful generation of KVLFF loaded NPs that, without significant effects on cell heath, are even more potent in reversing Aβ-induced pathologies compared to the free peptide. Therefore, NPs will significantly advance KVLFF treatment as a therapeutic option for AD.

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