Specific Peptide from the Novel W-Tau Isoform Inhibits Tau and Amyloid β Peptide Aggregation In Vitro.
Ontology highlight
ABSTRACT:
SUBMITTER: Cuadros R
PROVIDER: S-EPMC9264359 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The aggregation of tau protein is one of the hallmarks for Alzheimer's disease, resulting in neurodegeneration. The peptidomimetics strategy to prevent tau aggregation is more specific over other small molecules. In the present study, we analyzed the effect of amyloid-β-derived peptidomimetics for inhibiting heparin-induced tau aggregation in vitro. These peptides and their derivatives were known to prevent aggregation of amyloid-β. KLVFF is a hydrophobic sequence of the pentapeptide that prevented tau aggregation as observed by thioflavin S fluorescence, transmission electron microscopy, and circular dichroism spectroscopy. P4 and P5 also prevented assembly of tau into aggregates and formed short fibrils. The β-sheet breaker LPFFD was however ineffective in preventing tau aggregation. The peptides further demonstrated reversal of tau-induced cytotoxicity in a dose-dependent manner. Our results suggested that these peptides can also be used to inhibit tau aggregation and also, toxicity induced by tau could be considered as potential molecules that have an effect on tau as well as amyloid-β.
| S-EPMC8153954 | biostudies-literature
Project description:One of the hallmarks of the most common neurodegenerative disease, Alzheimer's disease (AD), is the extracellular deposition and aggregation of Amyloid Beta (Aβ)-peptides in the brain. Previous studies have shown that select metal ions, most specifically copper (Cu) and zinc (Zn) ions, have a synergistic effect on the aggregation of Aβ-peptides. In the present study, inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the metal content of a commercial recombinant human Aβ40 peptide. Cu and Zn were among the metals detected; unexpectedly, nickel (Ni) was one of the most abundant elements. Using a fluorescence-based assay, we found that Aβ40 peptide in vitro aggregation was enhanced by addition of Zn2+ and Ni2+, and Ni2+-induced aggregation was facilitated by acidic conditions. Nickel binding to Aβ40 peptide was confirmed by isothermal titration calorimetry. Addition of the Ni-specific chelator dimethylglyoxime (DMG) inhibited Aβ40 aggregation in absence of added metal, as well as in presence of Cu2+ and Ni2+, but not in presence of Zn2+. Finally, mass spectrometry analysis revealed that DMG can coordinate Cu or Ni, but not Fe, Se or Zn. Taken together, our results indicate that Ni2+ ions enhance, whereas nickel chelation inhibits, Aβ peptide in vitro aggregation. Hence, DMG-mediated Ni-chelation constitutes a promising approach towards inhibiting or slowing down Aβ40 aggregation.
| S-EPMC7988135 | biostudies-literature
Project description:A hallmark of Alzheimer's disease (AD) is the accumulation of tau protein in the brain. Compelling evidence indicates that the presence of tau aggregates causes irreversible neuronal destruction, eventually leading to synaptic loss. So far, the inhibition of tau aggregation has been recognized as one of the most effective therapeutic strategies. Cannabidiol (CBD), a major component found in Cannabis sativa L., has antioxidant activities as well as numerous neuroprotective features. Therefore, we hypothesize that CBD may serve as a potent substance to hamper tau aggregation in AD. In this study, we aim to investigate the CBD effect on the aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods in vitro and in silico. Using Thioflavin T (ThT) assay, circular dichroism (CD), and atomic force microscopy (AFM), we demonstrated that CBD can suppress tau fibrils formation. Moreover, by quenching assay, docking, and job's plot, we further demonstrated that one molecule of CBD interacts with one molecule of tau protein through a spontaneous binding. Experiments performed by quenching assay, docking, and Thioflavin T assay further established that the main forces are hydrogen Van der Waals and some non-negligible hydrophobic forces, affecting the lag phase of tau protein kinetics. Taken together, this study provides new insights about a natural substance, CBD, for tau therapy which may offer new hope for the treatment of AD.
| S-EPMC8700709 | biostudies-literature
Project description:BackgroundCurrent 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.ObjectiveThe 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.MethodsIn 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.ResultsIn the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ1-42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ1-42 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.ConclusionSuch converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ1-42 aggregation and treatment for Aβ-induced cognitive deficit.
| S-EPMC8293670 | biostudies-literature
Project description:Neurotoxic amyloid beta peptide (Abeta) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence Abeta accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Abeta clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). Abeta binding to apoE4 redirected the rapid clearance of free Abeta40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Abeta-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Abeta-apoE2 and Abeta-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Abeta-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Abeta were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, apoE isoforms differentially regulate Abeta clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.
| S-EPMC2582453 | biostudies-literature
Project description:The synthesis of a water/plasma soluble, noncytotoxic, "clicked" sugar-derivative of curcumin with amplified bioefficacy in modulating amyloid-β and tau peptide aggregation is presented. Curcumin inhibits amyloid-β and tau peptide aggregation at micromolar concentrations; the sugar-curcumin conjugate inhibits Aβ and tau peptide aggregation at concentrations as low as 8 nM and 0.1 nM, respectively. In comparison to curcumin, this conveniently synthesized Alzheimer's drug candidate is a more powerful antioxidant.
| S-EPMC3369720 | biostudies-literature
Project description:The aggregation of insoluble amyloid beta (Aβ) peptides in the brain is known to trigger the onset of neurodegenerative diseases, such as Alzheimer's disease. In spite of the massive number of investigations, the underlying mechanisms to destabilize the Aβ aggregates are still poorly understood. Some studies indicate the importance of oxidation to destabilize the Aβ aggregates. In particular, oxidation induced by cold atmospheric plasma (CAP) has demonstrated promising results in eliminating these toxic aggregates. In this paper, we investigate the effect of oxidation on the stability of an Aβ pentamer. By means of molecular dynamics simulations and umbrella sampling, we elucidate the conformational changes of Aβ pentamer in the presence of oxidized residues, and we estimate the dissociation free energy of the terminal peptide out of the pentamer form. The calculated dissociation free energy of the terminal peptide is also found to decrease with increasing oxidation. This indicates that Aβ pentamer aggregation becomes less favorable upon oxidation. Our study contributes to a better insight in one of the potential mechanisms for inhibition of toxic Aβ peptide aggregation, which is considered to be the main culprit to Alzheimer's disease.
| S-EPMC6445117 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfunction, and neuronal death.MethodsWe aimed to develop novel therapeutic D-amino acid peptides as Tau fibrillization inhibitors. It has been previously demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-peptides, and these characteristics may render them suitable for in vivo applications. Using a phage display procedure against wild type full-length Tau (TauFL), we selected a novel Tau binding L-peptide and synthesized its D-amino acid version ISAD1 and its retro inversed form, ISAD1rev, respectively.ResultsWhile ISAD1rev inhibited Tau aggregation only moderately, ISAD1 bound to Tau in the aggregation-prone PHF6 region and inhibited fibrillization of TauFL, disease-associated mutant full-length Tau (TauFLΔK, TauFL-A152T, TauFL-P301L), and pro-aggregant repeat domain Tau mutant (TauRDΔK). ISAD1 and ISAD1rev induced the formation of large high molecular weight TauFL and TauRDΔK oligomers that lack proper Thioflavin-positive β-sheet conformation even at lower concentrations. In silico modeling of ISAD1 Tau interaction at the PHF6 site revealed a binding mode similar to those known for other PHF6 binding peptides. Cell culture experiments demonstrated that ISAD1 and its inverse form are taken up by N2a-TauRDΔK cells efficiently and prevent cytotoxicity of externally added Tau fibrils as well as of internally expressed TauRDΔK.ConclusionsISAD1 and related peptides may be suitable for therapy development of AD by promoting off-pathway assembly of Tau, thus preventing its toxicity.
| S-EPMC8783508 | biostudies-literature
Project description:The aggregation or misfolding of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of Aβ aggregation is thought to be an effective strategy for AD treatment. The capability of a water-soluble porphyrin, 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit Aβ aggregation and to lower Aβ-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt Aβ aggregation but also disassemble the preformed Aβ aggregates. The atomic force microscopy imaging proves that TMPyP inhibits the formation of both oligomers and fibrils. Molecular dynamic simulations provide an insight into the interaction between TMPyP and Aβ at the molecular level. The half-maximal inhibitory concentrations of TMPyP acting on the oligomers and fibrils were determined to be 0.6 and 0.43 μM, respectively. As a member of porphyrin family, TMPyP is of rather low cytotoxicity, and the cytotoxicity of the Aβ aggregates was also relieved upon coincubation with TMPyP. The excellent performance of TMPyP thus makes it a potential drug candidate for AD therapy.
| S-EPMC6044923 | biostudies-literature
Project description:Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on the production of cerebral Aβ. A meta-analysis on humans showed moderate effects in the short term but no improvement in the Alzheimer's Disease Assessment Scale-Cognitive Subscale behavioral test. Here, we explore a potential direct effect of Ator on Aβ42 aggregation. Using NMR-based monomer consumption assays and CD spectroscopy, we observed a promoting effect of Ator in its original form (Ator-calcium) on Aβ42 aggregation, as expected because of the presence of calcium ions. The effect was reversed when applying a CaCO3-based calcium ion scavenging method, which was validated by the aforementioned methods as well as thioflavin-T fluorescence assays and transmission electron microscopy. We found that the aggregation was inhibited significantly when the concentration of calcium-free Ator exceeded that of Aβ by at least a factor of 2. The 1H-15N heteronuclear single quantum correlation and saturation-transfer difference NMR data suggest that calcium-free Ator exerts its effect through interaction with the 16KLVF19 binding site on the Aβ peptide via its aromatic rings as well as hydroxyl and methyl groups. On the other hand, molecular dynamics simulations confirmed that the increasing concentration of Ator is necessary for the inhibition of the conformational transition of Aβ from an α-helix-dominant to a β-sheet-dominant structure.
| S-EPMC8898965 | biostudies-literature