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 Epigallocatechin gallate: a review

2018 ◽  
Vol 63 (No. 10) ◽  
pp. 443-467 ◽  
Author(s):  
L. Bartosikova ◽  
J. Necas
Keyword(s):  
Green Tea ◽  
Epigallocatechin Gallate ◽  
Osteoporotic Fractures ◽  
Blood Cholesterol ◽  
Clinical Effects ◽  
Therapeutic Benefits ◽  
Wide Range ◽  
Anti Cancer

Epigallocatechin gallate is the major component of the polyphenolic fraction of green tea and is responsible for most of the therapeutic benefits of green tea consumption. A number of preclinical in vivo and in vitro experiments as well as clinical trials have shown a wide range of biological and pharmacological properties of polyphenolic compounds such as anti-oxidative, antimicrobial, anti-allergic, anti-diabetic, anti-inflammatory, anti-cancer, chemoprotective, neuroprotective and immunomodulatory effects. Epigallocatechin gallate controls high blood pressure, decreases blood cholesterol and body fat and decreases the risk of osteoporotic fractures. Further research should be performed to monitor the pharmacological and clinical effects of green tea and to more clearly elucidate its mechanisms of action and the potential for its use in medicine.

scholarly journals Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Luiza Fernandes ◽  
Thyago R. Cardim-Pires ◽  
Debora Foguel ◽  
Fernando L. Palhano
Keyword(s):  
Neurodegenerative Diseases ◽  
Green Tea ◽  
Epigallocatechin Gallate ◽  
Amyloid Β ◽  
The Elderly ◽  
New Therapeutic Approaches ◽  
Green Tea Polyphenol ◽  
Seed Propagation

The accumulation of protein aggregates in human tissues is a hallmark of more than 40 diseases called amyloidoses. In seven of these disorders, the aggregation is associated with neurodegenerative processes in the central nervous system such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aggregation occurs when certain soluble proteins lose their physiological function and become toxic amyloid species. The amyloid assembly consists of protein filament interactions, which can form fibrillar structures rich in β-sheets. Despite the frequent incidence of these diseases among the elderly, the available treatments are limited and at best palliative, and new therapeutic approaches are needed. Among the many natural compounds that have been evaluated for their ability to prevent or delay the amyloidogenic process is epigallocatechin-3-gallate (EGCG), an abundant and potent polyphenolic molecule present in green tea that has extensive biological activity. There is evidence for EGCG’s ability to inhibit the aggregation of α-synuclein, amyloid-β, and huntingtin proteins, respectively associated with PD, AD, and HD. It prevents fibrillogenesis (in vitro and in vivo), reduces amyloid cytotoxicity, and remodels fibrils to form non-toxic amorphous species that lack seed propagation. Although it is an antioxidant, EGCG in an oxidized state can promote fibrils’ remodeling through formation of Schiff bases and crosslinking the fibrils. Moreover, microparticles to drug delivery were synthesized from oxidized EGCG and loaded with a second anti-amyloidogenic molecule, obtaining a synergistic therapeutic effect. Here, we describe several pre-clinical and clinical studies involving EGCG and neurodegenerative diseases and their related mechanisms.

scholarly journals The inhibition of cellular toxicity of amyloid-β by dissociated transthyretin

2020 ◽  
Vol 295 (41) ◽  
pp. 14015-14024 ◽  
Author(s):  
Qin Cao ◽  
Daniel H. Anderson ◽  
Wilson Y. Liang ◽  
Joshua Chou ◽  
Lorena Saelices
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protective Effect ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Aβ Oligomers ◽  
Cellular Toxicity ◽  
Computational Docking

The protective effect of transthyretin (TTR) on cellular toxicity of β-amyloid (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aβ, a protein associated with Alzheimer's disease. TTR binds Aβ, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aβ oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

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 Epigallocatechin Gallate (EGCG), a Green Tea Polyphenol, Reduces Coronavirus Replication in a Mouse Model

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2533
Author(s):  
Rackhyun Park ◽  
Minsu Jang ◽  
Yea-In Park ◽  
Yeonjeong Park ◽  
Woochul Jung ◽  
...  
Keyword(s):  
Mouse Model ◽  
Green Tea ◽  
Particle Production ◽  
Epigallocatechin Gallate ◽  
Tea Polyphenols ◽  
Green Tea Polyphenols ◽  
Tea Polyphenol ◽  
Green Tea Polyphenol

The COVID-19 pandemic has resulted in a huge number of deaths from 2020 to 2021; however, effective antiviral drugs against SARS-CoV-2 are currently under development. Recent studies have demonstrated that green tea polyphenols, particularly EGCG, inhibit coronavirus enzymes as well as coronavirus replication in vitro. Herein, we examined the inhibitory effect of green tea polyphenols on coronavirus replication in a mouse model. We used epigallocatechin gallate (EGCG) and green tea polyphenols containing more than 60% catechin (GTP60) and human coronavirus OC43 (HCoV-OC43) as a surrogate for SARS-CoV-2. Scanning electron microscopy analysis results showed that HCoV-OC43 infection resulted in virion particle production in infected cells. EGCG and GTP60 treatment reduced coronavirus protein and virus production in the cells. Finally, EGCG- and GTP60-fed mice exhibited reduced levels of coronavirus RNA in mouse lungs. These results demonstrate that green tea polyphenol treatment is effective in decreasing the level of coronavirus in vivo.

scholarly journals Eriodictyol ameliorated cognitive dysfunction in APP/PS1 mice through inhibited ferroptosis via vitamin D receptor mediated Nrf2 activation

2021 ◽  
Author(s):  
Lin Li ◽  
Wenjun Li ◽  
Xiangru Zheng ◽  
Qinglong Liu ◽  
Qian Du ◽  
...  
Keyword(s):  
Vitamin D ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Vitamin D Receptor ◽  
Amyloid Β ◽  
Qpcr Assay ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background Alzheimer's disease (AD) is the most common type of neurodegenerative disease in contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound mainly exists in citrus fruits and some Chinese herbal medicine, has been reported with its effect of anti-inflammatory, antioxidant, anti-cancer and neuroprotective effects. However, there are few studies on the anti-AD effect and molecular mechanism of eriodictyol. Methods APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed by behavioral tests. The level of amyloid-β (Aβ) aggregation and hyper-phosphorylation of Tau in the brain of mice were detected by histological analysis and Western blotting. Meanwhile, HT-22 cells which induced by amyloid-β peptide (1-42) (Aβ1−42) oligomer were treated with eriodictyol after which cell viability was determined and the production of p-Tau was tested by Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4(GPX4), were determined both in vivo and in vitro by Fe straining, Western blotting and qPCR assay. Additionally, the expression level of Vitamin D receptor (VDR) and the activity of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested by Western blotting and qPCR assay. After that, the HT-22 cells with VDR knockout were used to explore the potential mechanisms and the relationship between VDR and Nrf2 was further assessed by coimmunoprecipitation assay and bioinformatics analysis. Results Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, suppressed Aβ aggregation and the phosphorylated level Tau in the brain of APP/PS1 mice. Meanwhile, eriodictyol could inhibit Tau hyper-phosphorylation and neurotoxicity in HT-22 cells induced by Aβ1−42 oligomer. Furthermore, both in vivo and in vitro, eriodictyol showed the anti-ferroptosis effect and its mechanism may connected with the activation of Nrf2/HO-1 signaling pathway. Additionally, the further experiment explains that the activation of Nrf2/HO-1 signaling pathway with eriodictyol treatment mediated by VDR. Conclusions Eriodictyol alleviated memory impairment and AD-like pathological changes via activating Nrf2/HO-1 signaling pathway mediated by VDR, which provide a new possibility for the treatment of AD.

scholarly journals CERTL Reduces C16 Ceramide, Amyloid-β Levels and Inflammation in a Model of Alzheimer's Disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Deregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction animal were challenged with behavior tests for memory, anxiety and locomotion. At week twelve brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male transgenic mice, modelling familial AD (5xFAD). CERTL in vivo over-expression has a mild effect on animal locomotion and decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

Investigation of anti-Alzheimer’s activity of aqueous extract of areca nuts (Areca catechu L.): In vitro and in vivo studies

2021 ◽  
Vol 20 (4) ◽  
pp. 406-415
Author(s):  
Mahboubeh Bozorgi ◽  
◽  
Zahra Najafi ◽  
Sahar Omidpanah ◽  
Arash Sadri ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
In Vivo Studies ◽  
Memory Impairments ◽  
Age Related ◽  
Areca Catechu ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer’s activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid β (Aβ) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.

Green tea polyphenols and its constituent epigallocatechin gallate inhibits proliferation of human breast cancer cells in vitro and in vivo

2007 ◽  
Vol 245 (1-2) ◽  
pp. 232-241 ◽  
Author(s):  
Rajesh L. Thangapazham ◽  
Anoop K. Singh ◽  
Anuj Sharma ◽  
James Warren ◽  
Jaya P. Gaddipati ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Green Tea ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Epigallocatechin Gallate ◽  
Green Tea Polyphenols ◽  
Human Breast Cancer Cells ◽  
Human Breast
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