A computational study of self-assembled hexapeptide inhibitors against amyloid-β (Aβ) aggregation

2017 ◽  
Vol 19 (1) ◽  
pp. 155-166 ◽  
Author(s):  
Yuan Qiao ◽  
Mingzhen Zhang ◽  
Ya'nan Liang ◽  
Jie Zheng ◽  
Guizhao Liang
Keyword(s):  
Computational Study ◽  
Amyloid Β ◽  
Structure Dynamics ◽  
Aβ Aggregation ◽  
Self Assembled

We explore the structure, dynamics, and interaction between 3 identified hexapeptides and different Aβ-derived fragments and an Aβ17–42 pentamer.

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 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 Cu-Based Turn-on Fluorescent Sensors for Cu-rich Amyloid β Aggregates

2021 ◽  
Author(s):  
Yiran Huang ◽  
Liang Sun ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescence Imaging ◽  
Protein Misfolding ◽  
Picolinic Acid ◽  
Amyloid Β ◽  
Fluorescent Sensors ◽  
Aβ Oligomers ◽  
Turn On ◽  
Aβ Aggregation

<div>Protein misfolding and metal dishomeostasis are two key</div><div>pathological factors of Alzheimer’s disease. Previous studies have showed that Cu‐mediated Aβ aggregation pathways lead to formation of neurotoxic Aβ oligomers. Herein, we reported a series of picolinic acid‐based Cu‐activatable sensors, which can be used for the fluorescence imaging of Cu‐rich Aβ aggregates.</div>

scholarly journals Computational investigation on the role of C-Terminal of human albumin on the dimerization of Aβ1-42 peptide

2020 ◽  
Vol 10 (1) ◽  
pp. 4944-4955 ◽  
Keyword(s):  
Computational Study ◽  
Binding Free Energy ◽  
Conformational Dynamics ◽  
Human Albumin ◽  
Potential Of Mean Force ◽  
Amber Force Field ◽  
Aβ Aggregation ◽  
The Difference ◽  
Dynamics Simulations

Alzheimer’s disease (AD) is characterized by the presence of Amyloid-beta (Aβ) peptide, which has the propensity to fold into β-sheets under stress forming aggregated amyloid plaques. Nowadays many studies have focused on the development of novel, specific therapeutic strategies to slow down Aβ aggregation or control preformed aggregates. Albumin, the most abundant protein in the cerebrospinal fluid, was reported to bind Aβ impeding its aggregation. Recently, it has been reported that C-terminal (CTerm) of Human Albumin binds with Aβ1-42, impairs Aβ aggregation and promotes disassembly of Aβ aggregates protecting neurons. In this computational study, we have investigated the effect of CTerm on the conformational dynamics and the aggregation propensity of Aβ1-42 peptide. We have performed molecular dynamics simulations on the Aβ1-42-Aβ1-42 homodimer and Aβ1-42-CTerm of albumin heterodimer using the AMBER force field ff99SBildn. From the Potential of mean force (PMF) study and Binding free energy (BFE) analysis, we observed the association of Aβ1-42 peptide monomer with itself in the form of homodimer to be stronger than its association with the CTerm in the heterodimer complex. The difference in the number of residues in the Aβ1-42 peptide monomer (42 AAs) and CTerm (35 AAs) may be probable reason for the difference in association between the monomeric units in corresponding homodimer and heterodimer complexes. But even then CTerm shows a significant effect on the dimerization of Aβ1-42 peptide. Our findings therefore suggest that CTerm can be used for the disassembly of Aβ1-42 peptide monomer.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Annona atemoya leaf extract ameliorates cognitive impairment in amyloid-β injected Alzheimer’s disease-like mouse model

2019 ◽  
Vol 244 (18) ◽  
pp. 1665-1679 ◽  
Author(s):  
Hye-Sun Lim ◽  
Yu Jin Kim ◽  
Eunjin Sohn ◽  
Jiyeon Yoon ◽  
Bu-Yeo Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cell Death ◽  
Growth Factor Receptor ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Bioactive Compound ◽  
Aβ Aggregation ◽  
Epidermal Growth ◽  
G Protein Coupled

Annona atemoya is a hybrid of Annona squamosa and Annona cherimola that grow in several subtropical or tropical areas such as Florida in the US, Philippines, Cuba, Jamaica, Taiwan, and Jeju in South Korea. We report that the A. atemoya leaves (AAL) have inhibitory effects on the pathogenesis and regulatory mechanisms of Alzheimer’s disease (AD). Ethanol extract of AAL prevented amyloid-β (Aβ) aggregation and increased free radical scavenging activity. In addition, AAL extract exerted protective effects against neuronal cell death in HT22 hippocampal cells. Moreover, oral administration of AAL extract significantly improved memory loss in the passive avoidance task and Y-maze test, as well as downregulated the expression of neuronal markers neuronal nuclei and brain-derived neurotrophic factor in Aβ-injected AD mice. To verify the molecular mechanisms responsible for anti-AD actions of AAL, we conducted the antibody microarray analysis and found that epidermal growth factor receptor/G protein-coupled receptor kinase 2 signaling was activated in neuronal cells and AD-like mouse models. Additionally, quantitative analyses of the six standard compounds using high-performance liquid chromatography revealed that rutin is the most abundant compound of AAL. Furthermore, efficacy analyses of six standard compounds showed that rutin and isoquercitrin had significant inhibitory activity on Aβ aggregation. Taken together with biological activity and the content of compounds, rutin maybe a bioactive compound of AAL in the AD pathogenesis. Overall, our findings provide the first scientific support for the therapeutic effects of AAL in AD and AD-related disorders. Impact statement Our study was aimed to find a novel candidate drug for Alzheimer’s disease (AD) using natural products. We assessed the effects of Annona atemoya extracts on crucial events in the pathogenesis of AD. A. atemoya leaf (AAL) extract significantly inhibited amyloid-β aggregation, oxidative stress, neuronal cell death, and memory impairment through the epidermal growth factor receptor/G protein-coupled receptor kinase 2 pathway. Simultaneous analysis using HPLC determined six standard compounds of AAL extract, and rutin was identified as a bioactive compound. Of note, the anti-AD activity of AAL extract was more significant compared to other extracts from medicinal plants of which efficacy was previously reported. The potential of AAL extract as an anti-AD agent may provide insight into the new drug development for AD treatment.

scholarly journals TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yao-Hsiang Shih ◽  
Ling-Hsien Tu ◽  
Ting-Yu Chang ◽  
Kiruthika Ganesan ◽  
Wei-Wei Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
Term Potentiation ◽  
Spatial Memory Deficit ◽  
Aβ Aggregation ◽  
Intrahippocampal Injection

AbstractTDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.

scholarly journals Polyphenols with Anti-Amyloid β Aggregation Show Potential Risk of Toxicity Via Pro-Oxidant Properties

2020 ◽  
Vol 21 (10) ◽  
pp. 3561 ◽  
Author(s):  
Hatasu Kobayashi ◽  
Mariko Murata ◽  
Shosuke Kawanishi ◽  
Shinji Oikawa
Keyword(s):  
Potential Risk ◽  
Deleterious Effect ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Chemical Compounds ◽  
Inhibitory Effect ◽  
Point Of View ◽  
Considerable Evidence ◽  
Naturally Occurring ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is the most common form of dementia among older people. Amyloid β (Aβ) aggregation has been the focus for a therapeutic target for the treatment of AD. Naturally occurring polyphenols have an inhibitory effect on Aβ aggregation and have attracted a lot of attention for the development of treatment strategies which could mitigate the symptoms of AD. However, considerable evidence has shown that the pro-oxidant mechanisms of polyphenols could have a deleterious effect. Our group has established an assay system to evaluate the pro-oxidant characteristics of chemical compounds, based on their reactivity with DNA. In this review, we have summarized the anti-Aβ aggregation and pro-oxidant properties of polyphenols. These findings could contribute to understanding the mechanism underlying the potential risk of polyphenols. We would like to emphasize the importance of assessing the pro-oxidant properties of polyphenols from a safety point of view.

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.

Sign in / Sign up

Export Citation Format

Share Document