Chalcones acting as inhibitors of cholinesterases, β-secretase and βamyloid aggregation and other targets for Alzheimer’s disease: a critical review

2020 ◽  
Vol 27 ◽  
Author(s):  
Giorgio Antoniolli ◽  
Wanda P. Almeida ◽  
Camila C. Frias ◽  
Tiago B. de Oliveira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physicochemical Properties ◽  
Water Solubility ◽  
Amyloid Peptide ◽  
Beta Secretase ◽  
Progressive Neurodegeneration ◽  
Severity Of The Disease ◽  
Number Of Publications ◽  
The Given

Background: Alzheimer's disease (AD) is an irreversible and progressive neurodegeneration, with a multifactorial pathophysiology, including cholinergic deficit, amyloid plaques, neurofibrillary tangles, oxidative stress, and neurodegeneration. Despite the severity of the disease, the therapeutic arsenal is limited, arousing the interest of researchers to search for substances that can act on these markers. Objective: In this review, we highlight some relevant points: the ability of chalcones to act on different targets related to the pathophysiology of Alzheimer's disease: cholinesterases, amyloid peptide, beta-secretase and other biomarkers. Method: This mini-review covered the literature concerning chalcones bioactivity from 2010 until now. In addition to the theoretical review, we included the prediction of physicochemical properties, using SwissADME software. Results: We found that the majority of the chalcones have been tested against cholinesterases, with moderate to good potencies, but in recent years, the number of publications related to targets of the amyloid hypothesis has been growing. Regarding the physicochemical properties, chalcones have a good profile, except the water solubility, which is not favorable. Conclusion: The most important characteristic of these molecules,is the given that many of the examples mentioned here act on more than one target, characterizing them as multi-target compounds. Regarding predicted properties, solubility stands out as the most problematic one, however these structures can incorporate functional groups that circumvent this problem of solubility without interfering in the biological activity.

scholarly journals Screening of Some Sulfonamide and Sulfonylurea Derivatives as Anti-Alzheimer’s Agents Targeting BACE1 and PPARγ

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
Ning Li ◽  
Yan Wang ◽  
Wensheng Li ◽  
Haiyan Li ◽  
Liu Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Management ◽  
Virtual Screening ◽  
Physicochemical Properties ◽  
Binding Site ◽  
Docking Studies ◽  
Common Type ◽  
Beta Secretase ◽  
Agonistic Activity

In the last few decades, Alzheimer’s disease (AD) has emerged as a serious global problem, and it has been considered as the most common type of dementia. PPARγ and beta-secretase 1 (BACE1) are considered as potential targets for Alzheimer’s disease management. In the same time, sulfonylureas and sulfonamides have been confirmed to have PPARγ agonistic activity. Aiming to obtain new anti-AD agents, thirty-five compounds of sulfonamide and sulfonylurea derivatives having the same essential pharmacophoric features of the reported PPARγ agonists have been subjected to virtual screening. Docking studies revealed that five compounds (1, 2, 3, 4, and 5) have promising affinities to PPARγ. They were also docked into the binding site of BACE1. In addition, ADMET and physicochemical properties of these compounds were considered. Additionally, these compounds were further evaluated against BACE1 and PPARγ. Compound 2 showed IC50 value of 1.64 μM against BACE1 and EC50 value of 0.289 μM against PPARγ.

scholarly journals Anti-Aggregation Property of Allicin by In Vitro and Molecular Docking Studies

2019 ◽  
Vol 13 ◽  
pp. 117906951986618 ◽  
Author(s):  
Suresh Kumar ◽  
Shivani Kumar ◽  
Heera Ram
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Molecular Interaction ◽  
Fibril Formation ◽  
Amyloid Peptide ◽  
Peptide Aggregation ◽  
Aβ Peptide ◽  
In Silico Studies

Amyloidogenesis is the process in which amyloid beta (Aβ) peptide aggregation results in plaque formation in central nervous system (CNS) are associated with many neurological diseases such as Alzheimer’s disease. The peptide aggregation initiated from peptide monomers results in formation of dimers, tetramers, fibrils, and protofibrils. The ability of allicin, a lipid-soluble volatile organosulfur biological compound, present in freshly crushed garlic ( Allium sativum L.) to inhibit fibril formation by the Aβ peptide in vitro was investigated in the present study. Inhibition of fibrillogenesis was measured by a Thioflavin T (ThT) fluorescence assay and visualized by transmission electron microscopy (TEM). The molecular interaction between allicin and Aβ peptide was also demonstrated by in silico studies. The results show that allicin strongly inhibited Aβ fibrils by 97% at 300 µM, compared with control (Aβ only) ( P < .001). These results were further validated by visual of fibril formation by transmission microscopy and molecular interaction of amyloid peptide with allicin by molecular docking. Aβ forms favourable hydrophobic interaction with Ile32, Met35, Val36, and Val39, and oxygen of allicin forms hydrogen bond with the amino acid residue Lys28. Allicin anti-amyloidogenic property suggests that this naturally occurring compound may have potential to ameliorate and prevent Alzheimer’s disease.

Pentapeptide Amides Interfere with the Aggregation of β-Amyloid Peptide of Alzheimer's Disease

2002 ◽  
Vol 292 (4) ◽  
pp. 931-936 ◽  
Author(s):  
Csaba Hetényi ◽  
Zoltán Szabó ◽  
Éva Klement ◽  
Zsolt Datki ◽  
Tamás Körtvélyesi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Peptide ◽  
Β Amyloid ◽  
Β Amyloid Peptide

scholarly journals The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-βProduction in Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Li Zuo ◽  
Benjamin T. Hemmelgarn ◽  
Chia-Chen Chuang ◽  
Thomas M. Best
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Treatment Options ◽  
Memory Loss ◽  
The United States ◽  
Traditional Medicines ◽  
Progressive Neurodegeneration ◽  
Antioxidant Supplements

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer’s disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβoverproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβplaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.

Natural product-based nanomedicine: Recent advances and issues for the treatment of Alzheimer's disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Choy Ker Woon ◽  
Wong Kah Hui ◽  
Razif Abas ◽  
Muhammad Huzaimi Haron ◽  
Srijit Das ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Medicinal Plants ◽  
Drug Transport ◽  
The Elderly ◽  
Current Evidence ◽  
Alternative Approach ◽  
Progressive Neurodegeneration ◽  
The Brain

: Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and its severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano- sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material’s bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicine-based approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.

scholarly journals Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Katsumi Matsuzaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physicochemical Properties ◽  
Lipid Rafts ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Pivotal Role ◽  
Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

scholarly journals Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

2005 ◽  
Vol 171 (1) ◽  
pp. 87-98 ◽  
Author(s):  
W. Haung Yu ◽  
Ana Maria Cuervo ◽  
Asok Kumar ◽  
Corrinne M. Peterhoff ◽  
Stephen D. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Survival ◽  
Mammalian Target Of Rapamycin ◽  
Amyloid Peptide ◽  
Survival Pathways ◽  
Secretase Activity ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Β Amyloid Peptide

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

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