Interactions des ions métalliques avec des formes tronquées du peptide amyloïde-bêta liées à la maladie d'Alzheimer

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Cu(II) binding to various forms of amyloid-β peptides. Are they friends or foes ?

International audienceIn the present micro-review, we describe the Cu(II) binding to several forms of amyloid-β peptides, the peptides involved in Alzheimer's disease. It has indeed been shown that in addition to the " full-length " peptide originating from the precursor protein after cleavage at position 1, several other shorter peptides do exist in large proportion and may be involved in the disease as well. Cu(II) binding to amyloid-β peptides is one of the key interactions that impact both the aggregating properties of the amyloid peptides and the Reactive Oxygen Species (ROS) production, two events linked to the etiology of the disease. Binding sites and affinity are described in correlation with Cu(II) induced ROS formation and Cu(II) altered aggregation, for amyloid peptides starting at position 1, 3, 4, 11 and for the corresponding pyroglutamate forms when they could be obtained (i.e. for peptides cleaved at positions 3 and 11). It appears that the current paradigm which points out a toxic role of the Cu(II) – amyloid-β interaction might well be shifted towards a possible protective role when the peptides considered are the N-terminally truncated ones

Biomaterials for Three-Dimensional Cell Culture: From Applications in Oncology to Nanotechnology

International audienceThree-dimensional cell culture has revolutionized cellular biology research and opened the door to novel discoveries in terms of cellular behavior and response to microenvironment stimuli. Different types of 3D culture exist today, including hydrogel scaffold-based models, which possess a complex structure mimicking the extracellular matrix. These hydrogels can be made of polymers (natural or synthetic) or low-molecular weight gelators that, via the supramolecular assembly of molecules, allow the production of a reproducible hydrogel with tunable mechanical properties. When cancer cells are grown in this type of hydrogel, they develop into multicellular tumor spheroids (MCTS). Three-dimensional (3D) cancer culture combined with a complex microenvironment that consists of a platform to study tumor development and also to assess the toxicity of physico-chemical entities such as ions, molecules or particles. With the emergence of nanoparticles of different origins and natures, implementing a reproducible in vitro model that consists of a bio-indicator for nano-toxicity assays is inevitable. However, the maneuver process of such a bio-indicator requires the implementation of a repeatable system that undergoes an exhaustive follow-up. Hence, the biggest challenge in this matter is the reproducibility of the MCTS and the associated full-scale characterization of this system’s components

Biomaterials for Three-Dimensional Cell Culture: From Applications in Oncology to Nanotechnology

Three-dimensional cell culture has revolutionized cellular biology research and opened the door to novel discoveries in terms of cellular behavior and response to microenvironment stimuli. Different types of 3D culture exist today, including hydrogel scaffold-based models, which possess a complex structure mimicking the extracellular matrix. These hydrogels can be made of polymers (natural or synthetic) or low-molecular weight gelators that, via the supramolecular assembly of molecules, allow the production of a reproducible hydrogel with tunable mechanical properties. When cancer cells are grown in this type of hydrogel, they develop into multicellular tumor spheroids (MCTS). Three-dimensional (3D) cancer culture combined with a complex microenvironment that consists of a platform to study tumor development and also to assess the toxicity of physico-chemical entities such as ions, molecules or particles. With the emergence of nanoparticles of different origins and natures, implementing a reproducible in vitro model that consists of a bio-indicator for nano-toxicity assays is inevitable. However, the maneuver process of such a bio-indicator requires the implementation of a repeatable system that undergoes an exhaustive follow-up. Hence, the biggest challenge in this matter is the reproducibility of the MCTS and the associated full-scale characterization of this system’s components

Methods and techniques to study the bioinorganic chemistry of metal–peptide complexes linked to neurodegenerative diseases

International audienceThis article provides a review about the most common techniques used to study the interaction of metal ions with amyloidogenic peptides. It is addressed to researchers, who want to know what kind of techniques exists, the information which can be obtained, their advantages, limits and the demands concerning sample preparation etc. It is not addressed to specialists of these techniques as the physical principles of the techniques are nor given. First, a general overview is given about sample preparation and treatment, with focus on the metal ions Zn(II), Cu(I/II) and Fe(II/III) and the peptides amyloid-β (but also α-synuclein, prion etc.). Then the methods NMR, EPR, electrochemistry, optical spectroscopy, isothermal titration calorimetry, FTIR, X-ray absorption and mass spectrometry are treated

Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance

International audienceSeveral diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases and type II diabetes mellitus. Furthermore, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-β, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS production in the case of copper. In addition, a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been observed in vivo and could be relevant for the coordination of metal ions are also described

Zn impacts Cu coordination to amyloid-beta, the Alzheimer's peptide, but not the ROS production and the associated cell toxicity

ISI Document Delivery No.: 070SP Times Cited: 0 Cited Reference Count: 21 Alies, Bruno Sasaki, Isabelle Proux, Olivier Sayen, Stephanie Guillon, Emmanuel Faller, Peter Hureau, Christelle Royal soc chemistry CambridgeCombined coordination of Zn-II and Cu-I or Cu-II to the amyloid-beta peptide has been investigated using XANES, EPR and NMR spectroscopies. While ZnII does alter Cu-II binding to A beta, this has no effect on (A beta)Cu induced ROS production and associated cell toxicity

Self-Assembly of Nucleoside-Derived Low-Molecular-Weight Gelators: A Thermodynamics and Kinetics Study on Different Length Scales

International audienceBiocompatible materials are of paramount importance in numerous fields. Unlike chemically bridge polymer-based hydrogels, low-molecular-weight gelators can form a reversible hydrogel as their structures rely on noncovalent interaction. Although many applications with this type of hydrogel can be envisioned, we still lack their understanding due to the complexity of their self-assembly process and the difficulty in predicting their behaviors (transition temperature, gelation kinetics, the impact of solvent, etc.). In this study, we extend the investigations of a series of nucleosidederived gelators, which only differ by subtle chemical modifications. Using a multitechnique approach, we determined their thermodynamic and kinetic features on various scale (molecular to macro) in different conditions. Monitored at the supramolecular level by circular dichroism as well as macroscopic scales by rheology and turbidimetry, we found out that the sol-gel and gel-sol transitions are greatly dependent on the concentration and on the mechanisms that are probed. Self-assembly kinetics depends on hydrogel molecules and is modulated by temperature and solvent. This fundamental study provides insight on the impact of some parameters on the gelation process, such as concentration, cooling rate, and the nature of the solvent

Zinc(II) modulates specifically amyloid formation and structure in model peptides

International audienceMetal ions such as zinc and copper can have dramatic effects on the aggregation kinetics of and the structures formed by several amyloidogenic peptides/proteins. Depending on the identity of the amyloidogenic peptide/protein and the conditions, Zn(II) and Cu(II) can promote or inhibit fibril formation, and in some cases these metal ions have opposite effects. To better understand this modulation of peptide aggregation by metal ions, the impact of Zn(II) binding to three amyloidogenic peptides (Aβ14-23, Aβ11-23, and Aβ11-28) on the formation and structure of amyloid-type fibrils was investigated. Zn(II) was able to accelerate fibril formation for all three peptides as measured by thioflavin T fluorescence and transmission electron microscopy. The effects of Zn(II) on Aβ11-23 and Aβ11-28 aggregation were very different compared with the effects of Cu(II), showing that these promoting effects were metal-specific. X-ray absorption spectroscopy suggested that the Zn(II) binding to Aβ11-23 and Aβ11-28 is very different from Cu(II) binding, but that the binding is similar in the case of Aβ14-23. A model is proposed in which the different coordination chemistry of Zn(II) compared with Cu(II) explains the metal-specific effect on aggregation and the difference between peptides Aβ14-23 and Aβ11-23/Aβ11-28

Dynamics of Zn^II Binding as a Key Feature in the Formation of Amyloid Fibrils by Aβ11-28

Supramolecular assembly of peptides and proteins into amyloid fibrils is of multifold interest, going from materials science to physiopathology. The binding of metal ions to amyloidogenic peptides is associated with several amyloid diseases, and amyloids with incorporated metal ions are of interest in nanotechnology. Understanding the mechanisms of amyloid formation and the role of metal ions can improve strategies toward the prevention of this process and enable potential applications in nanotechnology. Here, studies on Zn^II binding to the amyloidogenic peptide Aβ11-28 are reported. Zn^II modulates the Aβ11-28 aggregation, in terms of kinetics and fibril structures. Structural studies suggest that Aβ11-28 binds Zn^II by amino acid residues Glu11 and His14 and that Zn^II is rapidly exchanged between peptides. Structural and aggregation data indicate that Zn^II binding induces the formation of the dimeric Zn^II₁(Aβ11-28)₂ species, which is the building block of fibrillar aggregates and explains why Zn^II binding accelerates Aβ11-28 aggregation. Moreover, transient Zn^II binding, even briefly, was enough to promote fibril formation, but the final structure resembled that of apo-Aβ11-28 amyloids. Also, seeding experiments, i.e., the addition of fibrillar Zn^II₁(Aβ11-28)₂ to the apo-Aβ11-28 peptide, induced aggregation but not propagation of the Zn^II₁(Aβ11-28)₂-type fibrils. This can be explained by the dynamic Zn^II binding between soluble and aggregated Aβ11-28. As a consequence, dynamic Zn^II binding has a strong impact on the aggregation behavior of the Aβ11-28 peptide and might be a relevant and so far little regarded parameter in other systems of metal ions and amyloidogenic peptides