Calprotectin influences the aggregation of metal-free and metal-bound amyloid-β by direct interaction.

Proteins from the S100 family perform numerous functions and may contribute to Alzheimer's disease (AD). Herein, we report the effects of S100A8/S100A9 heterooligomer calprotectin (CP) and the S100B homodimer on metal-free and metal-bound amyloid-β (Aβ; Aβ40 and Aβ42) aggregation in vitro. Studies performed with CP-Ser [S100A8(C42S)/S100A9(C3S) oligomer] indicate that the protein influences the aggregation profile for Aβ40 in both the absence and presence of metal ions [i.

Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer's Disease.

A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA and its structural analogues in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that DA and its rationally designed structural derivatives (1-6) based on DA's oxidative transformation are able to modulate multiple pathological elements found in AD [i.e.

Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's Disease.

Multiple pathogenic factors [e.g., amyloid-β (Aβ), metal ions, metal-bound Aβ (metal-Aβ), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD).

Strategic Design of 2,2'-Bipyridine Derivatives to Modulate Metal-Amyloid-β Aggregation.

The complexity of Alzheimer's disease (AD) stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. To identify the involvement of metal-bound amyloid-β (metal-Aβ) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aβ aggregation were developed. Herein, we report a new class of 2,2'-bipyridine (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aβ aggregation over metal-free Aβ analogue.

Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-β Peptides.

An amyloidogenic peptide, amyloid-β (Aβ), has been implicated as a contributor to the neurotoxicity of Alzheimer's disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aβ (Aβ and Aβ) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties.

Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors.

Alzheimer's disease (AD) is characterized by an imbalance between production and clearance of amyloid-β (Aβ) species. Aβ peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among the various Aβ species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of Aβ oligomers has been challenging due to their heterogeneous and metastable nature.

An Iridium(III) Complex as a Photoactivatable Tool for Oxidation of Amyloidogenic Peptides with Subsequent Modulation of Peptide Aggregation.

Aggregates of amyloidogenic peptides are involved in the pathogenesis of several degenerative disorders. Herein, an iridium(III) complex, Ir-1, is reported as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Ir-1 was rationally designed based on multiple characteristics, including 1) photoproperties leading to excitation by low-energy radiation; 2) generation of reactive oxygen species responsible for peptide oxidation upon photoactivation under mild conditions; and 3) relatively easy incorporation of a ligand on the Ir center for specific interactions with amyloidogenic peptides.

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals.

Endoplasmic Reticulum-Localized Iridium(III) Complexes as Efficient Photodynamic Therapy Agents via Protein Modifications.

Protein inactivation by reactive oxygen species (ROS) such as singlet oxygen ((1)O2) and superoxide radical (O2(•-)) is considered to trigger cell death pathways associated with protein dysfunction; however, the detailed mechanisms and direct involvement in photodynamic therapy (PDT) have not been revealed. Herein, we report Ir(III) complexes designed for ROS generation through a rational strategy to investigate protein modifications by ROS. The Ir(III) complexes are effective as PDT agents at low concentrations with low-energy irradiation (≤ 1 J cm(-2)) because of the relatively high (1)O2 quantum yield (> 0.

Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper.

Amyloidosis is a clinical disorder implicated with the formation of toxic amyloid aggregates. Despite their pathological significance, it is challenging to define the structural characteristics of amyloid oligomers owing to their metastable nature. Herein, we report structural and mechanistic investigations of human islet amyloid polypeptide (hIAPP) oligomers, found in type II diabetes mellitus, in both the absence and presence of disease-relevant metal ions [, Cu(ii) and Zn(ii)].

Supramolecular inhibition of amyloid fibrillation by cucurbit[7]uril.

Amyloid fibrils are insoluble protein aggregates comprised of highly ordered β-sheet structures and they are involved in the pathology of amyloidoses, such as Alzheimer's disease. A supramolecular strategy is presented for inhibiting amyloid fibrillation by using cucurbit[7]uril (CB[7]). CB[7] prevents the fibrillation of insulin and β-amyloid by capturing phenylalanine (Phe) residues, which are crucial to the hydrophobic interactions formed during amyloid fibrillation.

Host-guest chemistry in the gas phase: complex formation of cucurbit[6]uril with proton-bound water dimer.

The hydration of cucurbit[6]uril (CB[6]) in the gas phase is investigated using electrospray ionization traveling wave ion mobility mass spectrometry (ESI-TWIM-MS). Highly abundant dihydrated and tetrahydrated species of diprotonated CB[6] are found in the ESI-TWIM-MS spectrum. The hydration patterns of the CB[6] ion and the dissociation patterns of the hydrated CB[6] ion indicate that two water molecules are bound to each other, forming a water dimer in the CB[6] complex.

Probing conformational change of intrinsically disordered α-synuclein to helical structures by distinctive regional interactions with lipid membranes.

α-Synuclein (α-Syn) is an intrinsically disordered protein, whose fibrillar aggregates are associated with the pathogenesis of Parkinson's disease. α-Syn associates with lipid membranes and forms helical structures upon membrane binding. In this study, we explored the helix formation of α-Syn in solution containing trifluoroethanol using small-angle X-ray scattering and electrospray ionization ion mobility mass spectrometry.

Host-guest chemistry from solution to the gas phase: an essential role of direct interaction with water for high-affinity binding of cucurbit[n]urils.

An investigation of the host-guest chemistry of cucurbit[n]uril (CB[n], n = 6 and 7) with α,ω-alkyldiammonium guests (H2N(CH2)xNH2, x = 4, 6, 8, 10, and 12) both in solution and in the gas phase elucidates their intrinsic host-guest properties and the contribution of solvent water. Isothermal titration calorimetry and nuclear magnetic resonance measurements indicate that all alkyldiammonium cations have inclusion interactions with CB[n] except for the CB[7]-tetramethylenediamine complex in aqueous solution. The electrospray ionization of mixtures of CB[n] and the alkyldiammonium guests reflects their solution phase binding constants.

Probing conformational changes of ubiquitin by host-guest chemistry using electrospray ionization mass spectrometry.

We report mechanistic studies of structural changes of ubiquitin (Ub) by host-guest chemistry with cucurbit[6]uril (CB[6]) using electrospray ionization mass spectrometry (ESI-MS) combined with circular dichroism spectroscopy and molecular dynamics (MD) simulation. CB[6] binds selectively to lysine (Lys) residues of proteins. Low energy collision-induced dissociation (CID) of the protein-CB[6] complex reveals CB[6] binding sites.