Current understanding of metal-dependent amyloid-ß aggregation and toxicity.

The discovery of effective therapeutics targeting amyloid-ß (Aß) aggregates for Alzheimer's disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains, highly concentrated metals, such as copper and zinc, are found in senile plaques mainly composed of Aß aggregates. These metal ions are coordinated to Aß and affect its aggregation and toxicity profiles. In this review, we illustrate the current view on molecular insights into the assembly of Aß peptides in the absence and presence of metal ions as well as the effect of metal ions on their toxicity.

Controlling π-π Interactions of Highly Soluble Naphthalene Diimide Derivatives for Neutral pH Aqueous Redox Flow Batteries.

Organic redox-active molecules are a promising platform for designing sustainable, cheap, and safe charge carriers for redox flow batteries. However, radical formation during the electron-transfer process causes severe side reactions and reduces cyclability. This problem is mitigated by using naphthalene diimide (NDI) molecules and regulating their π-π interactions. The long-range π-stacking of NDI molecules, which leads to precipitation, is disrupted by tethering four ammonium functionalities, and the solubility approaches 1.5 m in water. The gentle π-π interactions induce clustering and disassembling of the NDI molecules during the two-electron transfer processes. When the radical anion forms, the antiferromagnetic coupling develops tetramer and dimer and nullifies the radical character. In addition, short-range-order NDI clusters at 1 m concentration are not precipitated but inhibit crossover. They are disassembled in the subsequent electron-transfer process, and the negatively charged NDI core strongly interacts with ammonium groups. These behaviors afford excellent RFB performance, demonstrating 98% capacity retention for 500 cycles at 25 mA cm-2 and 99.5% Coulombic efficiency with 2 m electron storage capacity.

Drug repurposing: small molecules against Cu(II)-amyloid-ß and free radicals.

Alzheimer's disease (AD) presents a complex pathology entangling numerous pathological factors, including amyloid-ß (Aß), metal ions, and reactive oxygen species (ROS). Increasing evidence reveals pathological connections among these distinct components in AD. For instance, the association between the amyloid cascade and metal ion hypotheses has introduced a novel pathogenic target: metal-bound Aß. Investigation of such interconnections requires substantial research and can be expedited by chemical reagents that are able to modify multiple pathogenic factors in AD. Drug repurposing is an efficient approach for rediscovering previously utilized molecules with desirable biological and pharmaceutical properties as chemical reagents. Herein, we report the evaluation of three pre-approved drug molecules, selected based on their chemical structure and properties, as chemical reagents that can be used for elucidating the complicated pathology of AD.

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-ß.

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer's disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that SP potentially interacts with amyloid-ß (Aß) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aß and metal-bound Aß (metal-Aß). Herein, we report, for the first time, that SP is capable of interacting with both Aß and metal ions and consequently affects the aggregation of metal-free Aß and metal-Aß. Moreover, incubation of SP with Aß in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aß and metal-Aß in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aß and metal-Aß aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aß and metal-Aß. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aß and metal-Aß is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.

Tunable regulatory activities of 1,10-phenanthroline derivatives towards acid sphingomyelinase and Zn(ii)-amyloid-ß.

We report a new series of small molecules able to achieve the tunability of modulatory activities against acid sphingomyelinase (ASM) and Zn(ii)-bound amyloid-ß [Zn(ii)-Aß], two pathological targets found in the brain affected by Alzheimer's disease. Rational tuning of the hydrophobicity and Zn(ii) binding affinity of the 1,10-phenanthroline (phen) framework successfully yielded compounds as chemical modulators for ASM (4 and 5), Zn(ii)-Aß (phen, 1, and 2), or both (3).

Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer's Disease.

We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (ii) interact with metal ions, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase. Such a framework with multifunctionality could be useful for developing chemical reagents to advance our understanding of multifaceted pathologies of neurodegenerative disorders, including Alzheimer's disease.

Link of impaired metal ion homeostasis to mitochondrial dysfunction in neurons.

Manganese, iron, copper, and zinc are observed to play essential roles in mitochondria. The overload and depletion of metal ions in mitochondria under pathological conditions, however, could disturb mitochondrial compartments and functions leading to cell death. In this review, we mainly summarize how impaired metal ion homeostasis affects mitochondrial systems, such as membrane potentials, the tricarboxylic acid cycle, oxidative phosphorylation, and glutathione metabolism. In addition, based on current findings, we briefly describe a recent understanding of the relationship among metal ion dysregulation, mitochondrial dysfunction, and the pathogeneses of neurodegenerative diseases.