scholarly journals RRY Inhibits Amyloid-β1–42 Peptide Aggregation and Neurotoxicity

2021 ◽  
pp. 1-17
Author(s):  
Xicui Sun ◽  
Songwei Duan ◽  
Anna Cao ◽  
Bryan Villagomez ◽  
Runxuan Lin ◽  
...  
Keyword(s):  
In Silico ◽  
Cognitive Deficit ◽  
Amyloid Β ◽  
In Vivo Studies ◽  
Amyloid Β Protein ◽  
Transmission Electron ◽  
Β Protein ◽  
Aβ Aggregation

Background: Current understanding of amyloid-β protein (Aβ) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer’s disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides. Objective: The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aβ1–42 aggregating inhibition and Aβ clearance. Methods: In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aβ, then evaluating its inhibition of aggregation of Aβ, and finally its rescuing cognitive deficit. Results: In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ 1–42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ 1–42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aβ1–42-induced cognitive deficit, reducing the Aβ1–42 load and increasing the dendritic spines in the transgenic mouse model. Conclusion: Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ 1–42 aggregation and treatment for Aβ-induced cognitive deficit.

scholarly journals Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo

2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yingxia Liang ◽  
Frank Raven ◽  
Joseph F. Ward ◽  
Sherri Zhen ◽  
Siyi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein

271 Pharmacological manipulation of Alzheimer's amyloid β protein in vitro and in vivo

1996 ◽  
Vol 17 (4) ◽  
pp. S68
Author(s):  
C.B. Eckman ◽  
C.-M. Prada ◽  
A. Fauq ◽  
S.G. Younkin
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Pharmacological Manipulation ◽  
Β Protein

scholarly journals The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jing Di ◽  
Ibrar Siddique ◽  
Zizheng Li ◽  
Ghattas Malki ◽  
Simon Hornung ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Muscle Strength ◽  
Mouse Model ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Tau Pathology ◽  
Behavioral Deficits ◽  
Β Protein

Abstract Background Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly. Methods To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology. Results CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures. Conclusions The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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.

Identification of two novel peptides with antioxidant activity and their potential in inhibiting amyloid-β aggregation in vitro

2019 ◽  
Vol 10 (2) ◽  
pp. 1191-1202 ◽  
Author(s):  
Yang Liu ◽  
Xiaoling Lin ◽  
Qingyong Li ◽  
Min Wang ◽  
Mao Zhou ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Inhibiting Activity ◽  
Β Protein ◽  
Aβ Aggregation

Two novel peptides WW4 and WW7 were evaluated for their antioxidant activity, membrane penetrance and inhibiting activity of amyloid-β protein (Aβ) aggregation.

scholarly journals The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

2020 ◽  
Author(s):  
Jing Di ◽  
Ibrar Siddique ◽  
Zizheng Li ◽  
Ghattas Malki ◽  
Simon Hornung ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Muscle Strength ◽  
Mouse Model ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Tau Pathology ◽  
Behavioral Deficits ◽  
Β Protein

Abstract Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3×Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for one month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3×Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left the question whether CLR01 affected tau in vivo directly or indirectly open.Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3- or 1.0-mg/Kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ) and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

scholarly journals Induction of Methionine-Sulfoxide Reductases Protects Neurons from Amyloid β-Protein Insults in Vitro and in Vivo

Biochemistry ◽  
2011 ◽  
Vol 50 (49) ◽  
pp. 10687-10697 ◽  
Author(s):  
Jackob Moskovitz ◽  
Panchanan Maiti ◽  
Dahabada H. J. Lopes ◽  
Derek B. Oien ◽  
Aida Attar ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Methionine Sulfoxide ◽  
Amyloid Β Protein ◽  
Methionine Sulfoxide Reductases ◽  
Β Protein

Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

2020 ◽  
Vol 26 ◽  
Author(s):  
John Chen ◽  
Andrew Martin ◽  
Warren H. Finlay
Keyword(s):  
Drug Delivery ◽  
In Silico ◽  
Local Drug Delivery ◽  
In Vivo Studies ◽  
Intranasal Drug Delivery ◽  
Nasal Sprays ◽  
In Silico Studies ◽  
Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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