Restoring cellular copper homeostasis in Alzheimer disease: a novel peptide shuttle is internalized by an ATP-dependent endocytosis pathway involving Rab5- and Rab14-endosomes.

CPPs, or Cell-Penetrating Peptides, offer invaluable utility in disease treatment due to their ability to transport various therapeutic molecules across cellular membranes. Their unique characteristics, such as biocompatibility and low immunogenicity, make them ideal candidates for delivering drugs, genes, or imaging agents directly into cells. This targeted delivery enhances treatment efficacy while minimizing systemic side effects.

Rationally Designed Cu(I) Ligand to Prevent CuAβ-Generated ROS Production in the Alzheimer's Disease Context.

In the context of Alzheimer's disease, copper (Cu) can be loosely bound to the amyloid-β (Aβ) peptide, leading to the formation of CuAβ, which can catalytically generate reactive oxygen species that contribute to oxidative stress. To fight against this phenomenon, the chelation therapy approach has been developed and consists of using a ligand able to remove Cu from Aβ and to redox-silence it, thus stopping the reactive oxygen species (ROS) production. A large number of Cu(II) chelators has been studied, allowing us to define and refine the properties required to design a "good" ligand, but without strong therapeutic outcomes to date.

Redox processes in Cu-binding proteins: the "in-between" states in intrinsically disordered peptides.

We report on a concept that some of us first described a decade ago for pure electron transfer [V. Balland, C. Hureau and J.

Oxidative Damages on the Alzheimer's Related-Aβ Peptide Alters Its Ability to Assemble.

Oxidative stress that can lead to oxidation of the amyloid-β (Aβ) peptide is considered a key feature in Alzheimer's disease (AD), influencing the ability of Aβ to assemble into β-sheet rich fibrils that are commonly found in senile plaques of AD patients. The present study aims at investigating the fallouts of Aβ oxidation on the assembly properties of the Aβ peptide. To accomplish this, we performed kinetics and analysis on an oxidized Aβ (Aβ) peptide, resulting from the attack of reactive oxygen species (ROS) that are formed by the biologically relevant Cu/Aβ/dioxygen/ascorbate system.

Ability of Azathiacyclen Ligands To Stop Cu(Aβ)-Induced Production of Reactive Oxygen Species: [3N1S] Is the Right Donor Set.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that leads to the progressive and irreversible loss of mental functions. The amyloid beta (Aβ) peptide involved in the disease is responsible for the production of damaging reactive oxygen species (ROS) when bound to Cu ions. A therapeutic approach that consists of removing Cu ions from Aβ to alter this deleterious interaction is currently being developed.

Sequence-Activity Relationship of ATCUN Peptides in the Context of Alzheimer's Disease.

Amino-terminal Cu and Ni (ATCUN) binding sequences are widespread in the biological world. Here, we report on the study of eight ATCUN peptides aimed at targeting copper ions and stopping the associated formation of reactive oxygen species (ROS). This study was actually more focused on Cu(Aβ)-induced ROS production in which the Aβ peptide is the "villain" linked to Alzheimer's disease.

Development of Cu(ii)-specific peptide shuttles capable of preventing Cu-amyloid beta toxicity and importing bioavailable Cu into cells.

Copper (Cu) in its ionic forms is an essential element for mammals and its homeostasis is tightly controlled. Accordingly, Cu-dyshomeostasis can be lethal as is the case in the well-established genetic Wilson's and Menkes diseases. In Alzheimer's disease (AD), Cu-accumulation occurs in amyloid plaques, where it is bound to the amyloid-beta peptide (Aβ).

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer's-Related Aβ Peptide.

The progressive, neurodegenerative Alzheimer's disease (AD) is the most widespread dementia. Due to the ageing of the population and the current lack of molecules able to prevent or stop the disease, AD will be even more impactful for society in the future. AD is a multifactorial disease, and, among other factors, metal ions have been regarded as potential therapeutic targets.

Synthesis, characterization and superoxide dismutase activity of a biomimetic Mn(III) complex covalently anchored to mesoporous silica.

A mononuclear Mn(III) complex of a clickable ligand, [Mn(hbpapn)(HO)]ClO·4.5HO, where Hhbpapn = 1,3-bis[(2-hydroxybenzyl)(propargyl)amino]propane, has been prepared and fully characterized. The complex catalyzes the dismutation of superoxide employing a Mn(III)/Mn(IV) redox cycle, with catalytic rate constant of 3.

Synthesis, Structure, and Biologic Activity of Some Copper, Nickel, Cobalt, and Zinc Complexes with 2-Formylpyridine -Allylthiosemicarbazone.

A series of zinc(II) ([Zn(HO)(L)Cl] ()), copper (II) ([Cu(L)Cl] (), [Cu(L)Br] (), [Cu(L)(CHCOO)]·4HO ()), nickel(II) ([Ni()]Cl·HO ()), and cobalt(III) ([Co(L)]Cl ()) complexes were obtained with 2-formylpyridine -allylthiosemicarbazone (). In addition another two thiosemicarbazones (3-formylpyridine -allylthiosemicarbazone ( ) and 4-formylpyridine -allylthiosemicarbazone ( )) have been obtained. The synthesized thiosemicarbazones have been studied using H and C NMR spectroscopy, IR spectroscopy, and X-ray diffraction analysis.

Keggin-type polyoxometalates as Cu(II) chelators in the context of Alzheimer's disease.

Two Keggin polyoxometalates were used as new copper ligands to counteract the effects of Cu(Amyloid-β) interaction. Their ability to remove Cu from Cu(Amyloid-β), to stop Cu(Amyloid-β) induced formation of reactive oxygen species and to restore apo-like self-assembly of Cu(Amyloid-β) was shown.

Hybrid Bis-Histidine Phenanthroline-Based Ligands to Lessen Aβ-Bound Cu ROS Production: An Illustration of Cu(I) Significance.

We here report the synthesis of three new hybrid ligands built around the phenanthroline scaffold and encompassing two histidine-like moieties: phenHH, phenHGH and H'phenH', where H correspond to histidine and H' to histamine. These ligands were designed to capture Cu(I/II) from the amyloid-β peptide and to prevent the formation of reactive oxygen species produced by amyloid-β bound copper in presence of physiological reductant (e.g.

Solid-state and solution characterizations of [(TMPA)Cu(II)(SO)] and [(TMPA)Cu(II)(SO)] complexes: Application to sulfite and thiosulfate fast detection.

Sulfite (SO) and thiosulfate (SO) ions are used as food preservative and antichlor agent respectively. To detect low levels of such anions we used Cu(II) complex of the Tris-Methyl Pyridine Amine (TMPA) ligand, denoted L. Formation of [LCu(SO)] (1) and [LCu(SO)] (2) in solution were monitored using UV-Vis, EPR and cyclic voltammetry, while the solid-state X-ray structures of both complexes were solved.

A Water-Soluble Peptoid Chelator that Can Remove Cu from Amyloid-β Peptides and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease.

Cu bound to amyloid-β (Aβ) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimer's disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Aβ. This chelator should compete with Zn ions (Zn) that are present in the synaptic cleft while forming a nontoxic Cu complex.

Copper Imbalance in Alzheimer's Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology.

The cause of Alzheimer's disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease.

Measurement of Interpeptidic Cu Exchange Rate Constants of Cu-Amyloid-β Complexes to Small Peptide Motifs by Tryptophan Fluorescence Quenching.

The interpeptidic Cu exchange rate constants were measured for two Cu amyloid-β complexes, Cu(Aβ) and Cu(Aβ), to fluorescent peptides GHW and DAHW using a quantitative tryptophan fluorescence quenching methodology. The second-order rate constants were determined at three pH values (6.8, 7.

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

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.

Unexpected Trends in Copper Removal from Aβ Peptide: When Less Ligand Is Better and Zn Helps.

Cu, Zn, and amyloid-β (Aβ) peptides play an important role in the etiology of Alzheimer's disease (AD). Their interaction indeed modifies the self-assembly propensity of the peptide that is at the origin of the deposition of insoluble peptide aggregates in the amyloid plaque, a hallmark found in AD brains. Another even more important fallout of the Cu binding to Aβ peptide is the formation of reactive oxygen species (ROS) that contributes to the overall oxidative stress detected in the disease and is due to the redox ability of the Cu ions.

Concentration-Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides Aβ and Amylin*.

Invited for the cover of this issue are Jean-François Morfin and Éva Tóth at the CNRS in Orléans, and their collaborators from University of Debrecen, University of Coimbra and Université de Toulouse. The image depicts that when an amphiphilic compound is intravenously injected, monomer, pre-micellar and micellar forms can co-exist in the blood and have different affinities for amyloid peptides. Read the full text of the article at 10.

The Aggregation Pattern of Aβ is Altered by the Presence of N-Truncated Aβ and/or Cu in a Similar Way through Ionic Interactions.

Alzheimer's disease (AD) is one of the most common of the multifactorial diseases and is characterized by a range of abnormal molecular processes, such as the accumulation of extracellular plaques containing the amyloid-β (Aβ) peptides and dyshomeostasis of copper in the brain. In this study, we have investigated the effect of Cu on the aggregation of Aβ and Aβ , representing the two most prevalent families of Aβ peptides, that is, the full length and N-truncated peptides. Both families are similarly abundant in healthy and AD brains.

Impact of N-Truncated Aβ Peptides on Cu- and Cu(Aβ)-Generated ROS: Cu Matters!

In vitro Cu(Aβ )-induced ROS production has been extensively studied. Conversely, the ability of N-truncated isoforms of Aβ to alter the Cu-induced ROS production has been overlooked, even though they are main constituents of amyloid plaques found in the human brain. N-Truncated peptides at the positions 4 and 11 (Aβ and Aβ ) contain an amino-terminal copper and nickel (ATCUN) binding motif (H N-Xxx-Zzz-His) that confer them different coordination sites and higher affinities for Cu compared to the Aβ peptide.

Effect of coordination dissymmetry on the catalytic activity of manganese catalase mimics.

Two mixed-valence Mn(II)Mn(III) complexes, [MnL(OAc)(HO)]BPh·2.5HO and [MnL(OAc)]·4HO, obtained with unsymmetrical NO-hexadentate L (HL = 2-(N,N-bis(2-(pyridylmethyl)aminomethyl)-6-(N-(2-hydroxybenzyl)benzylaminomethyl)-4-methylphenol) and NO-heptadentate L (NaHL = 2-(N,N-bis(2-(pyridylmethyl)aminomethyl)-6-(N'-(2-hydroxybenzyl)(carboxymethyl)aminomethyl)-4-methylphenol sodium salt) ligands, have been prepared and characterized. Both complexes share a μ-phenolate-bis(μ-acetate)Mn(II)Mn(III) core and NO-coordination sphere around the Mn(II) ion, but differ in the donor groups surrounding Mn(III) (NO(solvent) and NO).

Concentration-Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides Aβ and Amylin*.

Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents. The attachment of a metal complex to amyloid recognition units typically leads to a decrease in peptide affinity. We show here that by separating a macrocyclic GdL chelate and a PiB targeting unit with a long hydrophobic C10 linker, it is possible to attain nanomolar affinities for both Aβ (K =4.

The aroylhydrazone INHHQ prevents memory impairment induced by Alzheimer's-linked amyloid-β oligomers in mice.

Converging evidence indicates that neurotoxicity and memory impairment in Alzheimer's disease is induced by brain accumulation of soluble amyloid-β oligomers (AβOs). Physiological metals are poorly distributed and concentrated in the senile plaques typical of Alzheimer's disease, where they may be coordinated to the amyloid-β peptide (Aβ). Indeed, zinc and copper increase Aβ oligomerization and toxicity.