scholarly journals Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2523 ◽  
Author(s):  
Éva Bartus ◽  
Gábor Olajos ◽  
Ildikó Schuster ◽  
Zsolt Bozsó ◽  
Mária Deli ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Early Stage ◽  
Amyloid Β ◽  
Titration Calorimetry ◽  
Protective Effects ◽  
Aβ Oligomers ◽  
Protein Targets ◽  
Drug Candidates ◽  
Viability Assay

Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding.

scholarly journals Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

2021 ◽  
Author(s):  
Liang Sun ◽  
Hong-Jun Cho ◽  
Soumyo Sen ◽  
Andres S. Arango ◽  
Truc T. Huynh ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
5Xfad Mice ◽  
Soluble Aβ Oligomers

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers <i>in vivo</i>, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the <sup>64</sup>Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these <i>in vitro</i> and <i>in vivo</i> studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

scholarly journals Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

2021 ◽  
Author(s):  
Liang Sun ◽  
Hong-Jun Cho ◽  
Soumyo Sen ◽  
Andres S. Arango ◽  
Truc T. Huynh ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
5Xfad Mice ◽  
Soluble Aβ Oligomers

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers <i>in vivo</i>, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the <sup>64</sup>Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these <i>in vitro</i> and <i>in vivo</i> studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

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 Steroidal glycoalkaloids fromSolanum nigrumtarget cytoskeletal proteins: anin silicoanalysis

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6012 ◽  
Author(s):  
Rumana Ahmad
Keyword(s):  
Binding Affinity ◽  
Anticancer Agents ◽  
Principal Component ◽  
Cytoskeletal Proteins ◽  
Hydroxyl Group ◽  
Docking Analysis ◽  
Drug Candidates ◽  
Division Cell

BackgroundSolanum nigrum(black nightshade;S. nigrum), a member of family Solanaceae, has been endowed with a heterogeneous array of secondary metabolites of which the steroidal glycoalkaloids (SGAs) and steroidal saponins (SS) have vast potential to serve as anticancer agents. Since there has been much controversy regarding safety of use of glycoalkaloids as anticancer agents, this area has remained more or less unexplored. Cytoskeletal proteins like actin play an important role in maintaining cell shape, synchronizing cell division, cell motility, etc. and along with their accessory proteins may also serve as important therapeutic targets for potential anticancer candidates. In the present study, glycoalkaloids and saponins fromS. nigrumwere screened for their interaction and binding affinity to cytoskeletal proteins, using molecular docking.MethodsBioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis were performed using softwares Molinspiration and Osiris Data Explorer respectively, to assess the feasibility of selected phytoconstituents as potential drug candidates. The results were compared with two standard reference drugs doxorubicin hydrochloride (anticancer) and tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA).ResultsDocking analysis revealed that the binding affinities of the phytoconstituents towards the target cytoskeletal proteins decreased in the order coronin>villin>ezrin>vimentin>gelsolin>thymosin>cofilin. Glycoalkaloid solasonine displayed the greatest binding affinity towards the target proteins followed by alpha-solanine whereas amongst the saponins, nigrumnin-I showed maximum binding affinity. PASS Analysis of the selected phytoconstituents revealed 1 to 3 violations of Lipinski’s parameters indicating the need for modification of their structure-activity relationship (SAR) for improvement of their bioactivity and bioavailability. Glycoalkaloids and saponins all had bioactivity scores between −5.0 and 0.0 with respect to various receptor proteins and target enzymes. Solanidine, solasodine and solamargine had positive values of druglikeness which indicated that these compounds have the potential for development into future anticancer drugs. Toxicity potential evaluation revealed that glycoalkaloids and saponins had no toxicity, tumorigenicity or irritant effect(s). SAR analysis revealed that the number, type and location of sugar or the substitution of hydroxyl group on alkaloid backbone had an effect on the activity and that the presence of α-L-rhamnopyranose sugar at C-2 was critical for a compound to exhibit anticancer activity.ConclusionThe present study revealed some cytoskeletal target(s) forS. nigrumphytoconstituents by docking analysis that have not been previously reported and thus warrant further investigations bothin vitroandin vivo.

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 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.

Thiosemicarbazonate complexes with affinity for amyloid-β fibers: synthesis, characterization and biological studies

2019 ◽  
Vol 11 (19) ◽  
pp. 2527-2546 ◽  
Author(s):  
Arantxa Pino-Cuevas ◽  
Paula D Raposinho ◽  
Célia Fernandes ◽  
António Paulo ◽  
Ulrich Abram ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Blood Brain Barrier ◽  
Free Ligand ◽  
Amyloid Β ◽  
Molecular Structures ◽  
X Ray Diffraction ◽  
X Ray ◽  
Biological Studies ◽  
Similar Affinity

Aim: Obtain radioimages of amyloid-β fibers using 99mTc-complexes. Methodology: Tridentate thiosemicarbazone and thiocarbonohydrazone ligands containing fragments (stilbene, azobenzene, benzothiazole or benzoxazole) with affinity for amyloid-ß fibers and its Re(I) complexes have been prepared. The molecular structures of several ligands and complexes were determined by x-ray diffraction. Binding affinity studies toward Aß1-42 fibers were performed for the ligands and Re(I) complexes. The ability of formation of some 99mTc(I) complexes, their biodistribution and in vivo stability have been established. Results & conclusion: Complexes of stilbene and benzothiazole thiosemicarbazonates show similar affinity for amyloid-β fibers to the free ligand. These 99mTc complexes present a reasonable in vivo stability and a low capability to cross the blood–brain barrier although not sufficient to brain amyloid imaging.

scholarly journals Neuropharmacological Effects of Quercetin: A Literature-Based Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Md. Shahazul Islam ◽  
Cristina Quispe ◽  
Rajib Hossain ◽  
Muhammad Torequl Islam ◽  
Ahmed Al-Harrasi ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuroprotective Effect ◽  
Animal Experiments ◽  
Amyloid Β ◽  
Neuronal Injury ◽  
Amyloid Β Peptide ◽  
Protective Effects ◽  
Neuroprotective Effects

Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer’s disease, Amyloid β peptide, Parkinson’s disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.

scholarly journals The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse AD Models

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1204
Author(s):  
Anaïs Bécot ◽  
Raphaëlle Pardossi-Piquard ◽  
Alexandre Bourgeois ◽  
Eric Duplan ◽  
Qingli Xiao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mouse Model ◽  
Early Stage ◽  
Amyloid Β ◽  
Newborn Mice ◽  
Cellular Models ◽  
In Vivo Experiments ◽  
Lysosome Biogenesis ◽  
Transcription Factor Eb

: Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Amyloid-β Inhibits PDGFβ Receptor Activation and Prevents PDGF-BBInduced Neuroprotection

2018 ◽  
Vol 15 (7) ◽  
pp. 618-627 ◽  
Author(s):  
Hui Liu ◽  
Golam T. Saffi ◽  
Maryam S. Vasefi ◽  
Youngjik Choi ◽  
Jeff S. Kruk ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
Receptor Activation ◽  
Cell Number ◽  
Physical Interaction ◽  
Protective Effects

Background: PDGFβ receptors and their ligand, PDGF-BB, are upregulated in vivo after neuronal insults such as ischemia. When applied exogenously, PDGF-BB is neuroprotective against excitotoxicity and HIV proteins. Objective: Given this growth factor's neuroprotective ability, we sought to determine if PDGF-BB would be neuroprotective against amyloid-β (1-42), one of the pathological agents associated with Alzheimer's disease (AD). Methods and Results: In both primary hippocampal neurons and the human-derived neuroblastoma cell line, SH-SY5Y, amyloid-β treatment for 24 h decreased surviving cell number in a concentrationdependent manner. Pretreatment with PDGF-BB failed to provide any neuroprotection against amyloid-β in primary neurons and only very limited protective effects in SH-SY5Y cells. In addition to its neuroprotective action, PDGF promotes cell growth and division in several systems, and the application of PDGFBB alone to serum-starved SH-SY5Y cells resulted in an increase in cell number. Amyloid-β attenuated the mitogenic effects of PDGF-BB, inhibited PDGF-BB-induced PDGFβ receptor phosphorylation, and attenuated the ability of PDGF-BB to protect neurons against NMDA-induced excitotoxicity. Despite the ability of amyloid-β to inhibit PDGFβ receptor activation, immunoprecipitation experiments failed to detect a physical interaction between amyloid-β and PDGF-BB or the PDGFβ receptor. However, G protein-coupled receptor transactivation of the PDGFβ receptor (an exclusively intracellular signaling pathway) remained unaffected by the presence of amyloid-β. Conclusions: As the PDGF system is upregulated upon neuronal damage, the ability of amyloid-β to inhibit this endogenous neuroprotective system should be further investigated in the context of AD pathophysiology.

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