scholarly journals Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

2020 ◽  
Vol 21 (3) ◽  
pp. 1129 ◽  
Author(s):  
Siddhartha Banerjee ◽  
Mohtadin Hashemi ◽  
Karen Zagorski ◽  
Yuri L. Lyubchenko
Keyword(s):  
Self Assembly ◽  
Membrane Surface ◽  
Amyloid Β ◽  
The Self ◽  
Bulk Solution ◽  
Aggregation Process ◽  
Physiological Concentration ◽  
Dynamics Simulations

The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer’s disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations - a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid formation of oligomers. The self-assembly process is reversible, so assembled aggregates can dissociate from the membrane surface into the bulk solution to further participate in the aggregation process. Molecular dynamics simulations demonstrate that the transient membrane-Aβ interaction dramatically changes the protein conformation, facilitating the assembly of dimers. The results indicate peptide–membrane interaction is the critical step towards oligomer formation at physiologically low protein concentrations.

scholarly journals Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

2019 ◽  
Author(s):  
Siddhartha Banerjee ◽  
Mohtadin Hashemi ◽  
Karen Zagorski ◽  
Yuri L. Lyubchenko
Keyword(s):  
Self Assembly ◽  
Lipid Membranes ◽  
Membrane Surface ◽  
Amyloid Β ◽  
Test Tube ◽  
Aggregation Process ◽  
Self Assembling ◽  
Nanoscale Aggregates

AbstractThe assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid β (Aβ) proteins is considered as a major cause for the development of Alzheimer’s disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that Aβ42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein. As a result, the misfolded Aβ42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.

scholarly journals Reproducibility Problems of Amyloid-β Self-Assembly and How to Deal With Them

2021 ◽  
Vol 8 ◽  
Author(s):  
Peter Faller ◽  
Christelle Hureau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Test Tube ◽  
The Self ◽  
Aggregation Process ◽  
Self Assembled

The self-assembly of peptides and proteins into amyloid fibrils and other aggregates are linked to several diseases. One of the most studied cases is the peptide amyloid-β (Aβ), found self-assembled in Alzheimer's disease patients' brains. In test tubes, assays with chemically synthesized or recombinant Aβ are widely investigated to understand the aggregation process and to find modulators, which could be of therapeutic interest. Experience over more than a decade in our laboratory through discussions with colleagues, expertly studying the literature, and as reviewers revealed to us the widely encountered difficulty to control the aggregation and obtain reproducible results in the test tube. However, this issue is scarcely reported and discussed in the publications, which we think hampers strongly the progress in this field and can deceive newcomers. Here, we describe the difficulty and potential reasons to obtain reproducible aggregation data and propose some guidelines for working with it.

scholarly journals Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors

2020 ◽  
Vol 2020 ◽  
pp. 1-23 ◽  
Author(s):  
Vincent Roy ◽  
Brice Magne ◽  
Maude Vaillancourt-Audet ◽  
Mathieu Blais ◽  
Stéphane Chabaud ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Tumor Microenvironment ◽  
Self Assembly ◽  
The Self ◽  
Human Organ ◽  
Assembly Method ◽  
Cancer Models ◽  
Organ Specific

Cancer research has considerably progressed with the improvement of in vitro study models, helping to understand the key role of the tumor microenvironment in cancer development and progression. Over the last few years, complex 3D human cell culture systems have gained much popularity over in vivo models, as they accurately mimic the tumor microenvironment and allow high-throughput drug screening. Of particular interest, in vitrohuman 3D tissue constructs, produced by the self-assembly method of tissue engineering, have been successfully used to model the tumor microenvironment and now represent a very promising approach to further develop diverse cancer models. In this review, we describe the importance of the tumor microenvironment and present the existing in vitro cancer models generated through the self-assembly method of tissue engineering. Lastly, we highlight the relevance of this approach to mimic various and complex tumors, including basal cell carcinoma, cutaneous neurofibroma, skin melanoma, bladder cancer, and uveal melanoma.

The Origin of the Eukaryotic Cell Based on Conservation of Existing Interfaces

2006 ◽  
Vol 12 (4) ◽  
pp. 513-523 ◽  
Author(s):  
Albert D. G. de Roos
Keyword(s):  
Plasma Membrane ◽  
Protein Interactions ◽  
Self Assembly ◽  
Evolutionary Model ◽  
Lipid Vesicles ◽  
Eukaryotic Cell ◽  
The Self ◽  
Lipid Protein Interactions

Current theories about the origin of the eukaryotic cell all assume that during evolution a prokaryotic cell acquired a nucleus. Here, it is shown that a scenario in which the nucleus acquired a plasma membrane is inherently less complex because existing interfaces remain intact during evolution. Using this scenario, the evolution to the first eukaryotic cell can be modeled in three steps, based on the self-assembly of cellular membranes by lipid-protein interactions. First, the inclusion of chromosomes in a nuclear membrane is mediated by interactions between laminar proteins and lipid vesicles. Second, the formation of a primitive endoplasmic reticulum, or exomembrane, is induced by the expression of intrinsic membrane proteins. Third, a plasma membrane is formed by fusion of exomembrane vesicles on the cytoskeletal protein scaffold. All three self-assembly processes occur both in vivo and in vitro. This new model provides a gradual Darwinistic evolutionary model of the origins of the eukaryotic cell and suggests an inherent ability of an ancestral, primitive genome to induce its own inclusion in a membrane.

scholarly journals Yeast proteins associated with microtubules in vitro and in vivo.

1992 ◽  
Vol 3 (1) ◽  
pp. 29-47 ◽  
Author(s):  
G Barnes ◽  
K A Louie ◽  
D Botstein
Keyword(s):  
Self Assembly ◽  
Synthetic Peptides ◽  
Immunofluorescence Microscopy ◽  
The Self ◽  
Microtubule Associated Proteins ◽  
Amino Terminal ◽  
Novel Proteins ◽  
Associated Proteins

Conditions were established for the self-assembly of milligram amounts of purified Saccharomyces cerevisiae tubulin. Microtubules assembled with pure yeast tubulin were not stabilized by taxol; hybrid microtubules containing substoichiometric amounts of bovine tubulin were stabilized. Yeast microtubule-associated proteins (MAPs) were identified on affinity matrices made from hybrid and all-bovine microtubules. About 25 yeast MAPs were isolated. The amino-terminal sequences of several of these were determined: three were known metabolic enzymes, two were GTP-binding proteins (including the product of the SAR1 gene), and three were novel proteins not found in sequence databases. Affinity-purified antisera were generated against synthetic peptides corresponding to two of the apparently novel proteins (38 and 50 kDa). Immunofluorescence microscopy showed that both these proteins colocalize with intra- and extranuclear microtubules in vivo.

Acidity-responsive shell-sheddable camptothecin-based nanofibers for carrier-free cancer drug delivery

Nanoscale ◽  
2019 ◽  
Vol 11 (34) ◽  
pp. 15907-15916 ◽  
Author(s):  
Zhuha Zhou ◽  
Ying Piao ◽  
Lingqiao Hao ◽  
Guanyu Wang ◽  
Zhuxian Zhou ◽  
...  
Keyword(s):  
Self Assembly ◽  
Surface Coating ◽  
Tumor Tissue ◽  
The Self ◽  
Cancer Drug ◽  
Ph Responsive ◽  
Carrier Free ◽  
Cancer Drug Delivery

pH-responsive nanofibers are obtained by the self-assembly of the camptothecin prodrug and surface-coating, which can efficiently enter cancer cells in vitro and penetrate deep into tumor tissue in vivo.

New insights about the self-aggregation of benzoporphyrin derivatives: A theoretical and experimental investigation

2018 ◽  
Vol 22 (04) ◽  
pp. 342-354 ◽  
Author(s):  
Gabriel B. Cesar ◽  
Diogo S. Pellosi ◽  
Douglas Vanzin ◽  
Renato S. Gonçalves ◽  
Wilker Caetano ◽  
...  
Keyword(s):  
Sodium Dodecyl ◽  
Ester Group ◽  
The Self ◽  
Van Der Waals Interactions ◽  
Molecular Volume ◽  
Aggregation Process ◽  
New Development ◽  
Self Aggregation

The self-aggregation process and its overcoming remain a barrier for the employment of many molecules as photosensitizers (PS) in photodynamic therapy (PDT). The B-ring isomer co-produced during the synthesis of the Verteporfin[Formula: see text] (A-ring) is an example. Although both isomers possess similar in vitro/in vivo efficiency, the strong and not well-understood self-aggregation process of the B-ring derivative impairs its clinical use. This paper reports the use of theoretical calculus and its correlation with experimental analysis to find the main differences between the A and B-ring isomers. For that purpose, micelles of Pluronic[Formula: see text] P-123 and Sodium Dodecyl Sulfate were chosen as simple membrane models and possible drug delivery system, as in the case of P-123. At physiological pH, the main reason for the high self-aggregation tendency is associated with the higher (22%) molecular volume of the B ring, which increases the van der Waals interactions. However, at mildly acidic conditions, the B ring possesses a shallow dihedral angle between the methyl ester group and the tetrapyrrolic macrocycle that favors the approach of units in the aggregate. These discrepancies directly affect the binding and stability of the isomers in the micelles. However, P-123 micelles were able to readily incorporate and monomerize/stabilize both PS over long periods. NOESY experiments confirmed a deep location of both PS inside P-123 micelles, which justifies their efficiency in preventing the self-aggregation process. These findings may substantiate new studies involving the marginalized B-ring isomers and encourage new development in formulations for their use in PDT.

scholarly journals Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions

2020 ◽  
Author(s):  
Ruoning Wang ◽  
Yujie Yang ◽  
Mengmeng Yang ◽  
Dandan Yuan ◽  
Jinyu Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Self Assembly ◽  
Metastatic Cancer ◽  
Metastatic Breast ◽  
Md Simulations ◽  
Intermolecular Forces ◽  
The Self

Abstract Background: The treatment of metastatic cancer continues to be very challenging worldwide. Notably, excipient-free nanodispersions that are entirely composed of pharmaceutically active molecules are regarded as promising candidates for the next generation of drug formulations. These molecules are mainly formulated from the self-assembly of drug molecules that enable the safe and effective delivery of therapeutic drugs to local diseased lesions. Herein, we developed a novel and green approach for preparing nanoparticles via the self-assembly of rhein (RHE) and doxorubicin (DOX) molecules, named RHE/DOX nanoparticles (RD NPs); this assembly was associated with π−π stacking interactions and did not involve any organic solvents. Results：Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around RHE molecules through intermolecular forces. With the advantage of nanosizing, RD NPs improved the intracellular drug retention of DOX. As a dual-drug-loaded nanoformulation, the toxicity of RD NPs to tumor cells in vitro was synergistically enhanced. The combination of DOX and RHE in nanoparticles exhibited a synergistic effect with a combination index (CI) value of 0.51 and showed a stronger ability to induce cell apoptosis compared to that of free DOX. Furthermore, RD NPs treatment not only effectively suppressed primary tumor growth but also successfully inhibited tumor metastasis both in vitro and in vivo, with a good safety profile. Conclusion: The generation of pure nanodrugs via a self-assembly approach might be an option and may provide inspiration for the fabrication of new excipient-free nanodispersions, especially for two small molecular antitumor drugs that could potentially have synergistic antiproliferation effects against metastatic breast cancer.

scholarly journals The Self-Assembly of a Cyclometalated Palladium Photosensitizer into Protein-Stabilized Nanorods Triggers Drug Uptake In Vitro and In Vivo

2020 ◽  
Vol 142 (23) ◽  
pp. 10383-10399
Author(s):  
Xue-Quan Zhou ◽  
Ming Xiao ◽  
Vadde Ramu ◽  
Jonathan Hilgendorf ◽  
Xuezhao Li ◽  
...  
Keyword(s):  
Self Assembly ◽  
The Self ◽  
Drug Uptake

scholarly journals Chemical Chaperones Modulate the Formation of Metabolite Assemblies

2021 ◽  
Vol 22 (17) ◽  
pp. 9172
Author(s):  
Hanaa Adsi ◽  
Shon A. Levkovich ◽  
Elvira Haimov ◽  
Topaz Kreiser ◽  
Massimiliano Meli ◽  
...  
Keyword(s):  
Self Assembly ◽  
Rational Design ◽  
Inhibitory Effect ◽  
Amyloid Formation ◽  
Inborn Errors ◽  
Chemical Chaperones ◽  
Dynamics Simulations ◽  
Fibril Morphology

The formation of amyloid-like structures by metabolites is associated with several inborn errors of metabolism (IEMs). These structures display most of the biological, chemical and physical properties of protein amyloids. However, the molecular interactions underlying the assembly remain elusive, and so far, no modulating therapeutic agents are available for clinical use. Chemical chaperones are known to inhibit protein and peptide amyloid formation and stabilize misfolded enzymes. Here, we provide an in-depth characterization of the inhibitory effect of osmolytes and hydrophobic chemical chaperones on metabolite assemblies, thus extending their functional repertoire. We applied a combined in vivo-in vitro-in silico approach and show their ability to inhibit metabolite amyloid-induced toxicity and reduce cellular amyloid content in yeast. We further used various biophysical techniques demonstrating direct inhibition of adenine self-assembly and alteration of fibril morphology by chemical chaperones. Using a scaffold-based approach, we analyzed the physiochemical properties of various dimethyl sulfoxide derivatives and their role in inhibiting metabolite self-assembly. Lastly, we employed whole-atom molecular dynamics simulations to elucidate the role of hydrogen bonds in osmolyte inhibition. Our results imply a dual mode of action of chemical chaperones as IEMs therapeutics, that could be implemented in the rational design of novel lead-like molecules.

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