The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System

Frontiers in Neuroscience, Год журнала: 2019, Номер 13

Опубликована: Янв. 22, 2019

The homeostasis of iron is fundamental importance in the central nervous system (CNS) to ensure biological processes such as oxygen transport, mitochondrial respiration or myelin synthesis. Dyshomeostasis and accumulation can be observed during aging both are shared characteristics several neurodegenerative diseases. Iron-mediated generation reactive species (ROS) may lead protein aggregation cellular toxicity. process misfolding neuronal proteins α-synuclein, Tau, amyloid beta (Aβ), TDP-43 SOD1 a common hallmark many disorders has been shown facilitate aggregation. Thus, both, aggregating proposed amplify their detrimental effects disease state. In this review, we give an overview on different involved neurodegeneration. Furthermore, discuss mechanisms iron-mediated toxicity emphasizing red-ox chemistry protein-binding properties iron. Finally, address current therapeutic approaches harnessing chelation disease-modifying intervention disorders, Parkinson's disease, Alzheimer's amyotrophic lateral sclerosis.

Язык: Английский

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Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity

iScience, Год журнала: 2020, Номер 23(4), С. 101005 - 101005

Опубликована: Март 25, 2020

Multiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathological devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity observed neuronal cells including generation reactive oxygen (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor ameliorate cellulo AD. The structural attributes polyphenolic Ber-D have contributed its efficient Cu chelation arresting redox cycle prevent ROS rescue biomacromolecules from oxidative damage. inhibits metal-dependent -independent aggregation, which supported by silico studies. treatment averts dysfunction corresponding contributing These key make potential therapeutic candidate

Язык: Английский

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Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer’s Disease Multitarget Drug Discovery?

Journal of Medicinal Chemistry, Год журнала: 2020, Номер 64(1), С. 26 - 41

Опубликована: Дек. 21, 2020

Alzheimer's disease (AD), like other multifactorial diseases, is the result of a systemic breakdown different physiological networks. As result, several lines evidence suggest that it could be more efficiently tackled by molecules directed toward dysregulated biochemical targets or pathways. In this context, selection to which new will crucial. For years, design such multitarget-directed ligands (MTDLs) has been based on main involved in "cholinergic" and "β-amyloid" hypothesis. Recently, there have some reports MTDLs targeting glycogen synthase kinase 3β (GSK-3β) enzyme, due its appealing properties. Indeed, enzyme tau hyperphosphorylation, controls multitude CNS-specific signaling pathways, establishes strict connections with factors implicated AD pathogenesis. present Miniperspective, we discuss reasons behind development GSK-3β-directed highlight recent efforts obtain these classes as potential disease-modifying agents.

Язык: Английский

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Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

Chemical Science, Год журнала: 2022, Номер 13(46), С. 13657 - 13689

Опубликована: Янв. 1, 2022

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and major contributor to dementia cases worldwide. AD clinically characterized by learning, memory, cognitive deficits. The accumulation of extracellular amyloid β (Aβ) plaques neurofibrillary tangles (NFTs) tau are the pathological hallmarks explored as targets for clinical diagnosis therapy. pathology poorly understood there no fully approved treatments. Notwithstanding gap, decades research in understanding mechanisms have revealed multifactorial nature AD. As result, multipronged holistic approaches pertinent targeting multiple biomarkers developing effective therapeutics. In this perspective, recent developments Aβ targeted diagnostic therapeutic tools discussed. Novel indirect, combination, circulating potential highlighted. We underline importance multiplexing multimodal detection generate biomarker fingerprints reliable strategy. classical therapeutics aggregation pathways described with bottlenecks Drug discovery efforts multifaceted toxicity involving protein aggregation, metal toxicity, oxidative stress, mitochondrial damage, neuroinflammation Recent focused on strategies rationally design multifunctional modulators factors presented future drug development discover

Язык: Английский

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Near-Infrared Fluorescent Probes as Imaging and Theranostic Modalities for Amyloid-Beta and Tau Aggregates in Alzheimer’s Disease

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(13), С. 8550 - 8595

Опубликована: Июнь 27, 2022

A person suspected of having Alzheimer's disease (AD) is clinically diagnosed for the presence principal biomarkers, especially misfolded amyloid-beta (Aβ) and tau proteins in brain regions. Existing radiotracer diagnostic tools, such as PET imaging, are expensive have limited availability primary patient screening pre-clinical animal studies. To change status quo, small-molecular near-infrared (NIR) probes been rapidly developed, which may serve an inexpensive, handy imaging tool to comprehend dynamics pathogenic progression AD assess therapeutic efficacy vivo. This Perspective summarizes biochemistry Aβ then focuses on structurally diverse NIR with coverages their spectroscopic properties, binding affinity toward species, theranostic effectiveness. With summarized information perspective discussions, we hope that this paper a guiding designing novel vivo fluoroprobes capabilities future.

Язык: Английский

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Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer’s Disease: Experimental and Computational Insights

ACS Omega, Год журнала: 2023, Номер 8(5), С. 4508 - 4526

Опубликована: Янв. 25, 2023

Alzheimer's disease (AD) is the most common form of dementia, affecting millions people around world. Even though causes AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks development have been related high concentration metal cations. These roles include participation these cations in production reactive oxygen species, which involved neuronal damage. In order avoid increment oxidative stress, multifunctional ligands used coordinate proposed as a possible treatment AD. this review, we present recent advances experimental and computational works aiming understand role two redox active essential transition-metal (Cu Fe) one nonbiological (Al) proposals on stop or revert damaging effects promoted by

Язык: Английский

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Visualization of the elevated levels of hypochlorous acid in Alzheimer's disease with a ruthenium(II) complex-based luminescence probe

Analytica Chimica Acta, Год журнала: 2023, Номер 1279, С. 341779 - 341779

Опубликована: Сен. 3, 2023

Язык: Английский

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Ratiometric Detection of Cu²⁺ Using a Luminol-Tb-GMP Nanoprobe with High Sensitivity and Selectivity

ACS Sustainable Chemistry & Engineering, Год журнала: 2018, Номер 6(7), С. 9333 - 9341

Опубликована: Май 26, 2018

A novel ratiometric fluorescent method for the detection of copper ions (Cu2+) based on stimulus-responsive dual-ligand lanthanide luminol-Tb-GMP coordination polymer nanoparticle (CPNP) probe is reported in this study. The CPNPs are composed Tb3+ as center metal and ligand GMP together with cofactor luminol ligands bridging ligands. In presence Cu2+, fluorescence GMP-Tb response moiety dynamically quenched, while used reference remains constant. Hence, monitoring Cu2+ can be achieved by measuring ratio at 430 nm (F430) wavelength to 547 (F547) spectra suspension. sensing approach, when coordinates a luminol/GMP unit, units located vicinity will also quenched. Thus, sensitivity highly improved due large number CPNPs. obtained limit low 4.2 nM (S/N = 3), which approximately 3 orders magnitude lower than that single (3.5 μM) without doping. linear range from 0.01 80 μM. Because directly linked CPNP molecule, serves strong chelating reagent common disturbances Hg2+ Ag+ almost completely eliminated, improving selectivity practical application little interference. present has been successfully applied river water, ascites, urine samples, indicating detect environmental water complexed biological samples.

Язык: Английский

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Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly

Angewandte Chemie International Edition, Год журнала: 2019, Номер 58(18), С. 5988 - 5993

Опубликована: Фев. 28, 2019

Protein misfolding and aberrant aggregations are associated with multiple prevalent intractable diseases. Inhibition of amyloid assembly is a promising strategy for the treatment amyloidosis. Reported here design synthesis reactive conjugated polymer, poly(p-phenylene vinylene) derivative, functionalized p-nitrophenyl esters (PPV-NP) it inhibits proteins, degrades preformed fibrils, reduces cytotoxicity in living cells. PPV-NP attached to proteins through hydrophobic interactions irreversible covalent linkage. also exhibited capacity eliminate Aβ plaques brain slices ex vivo assays. This work represents an innovative attempt inhibit protein pathogenic aggregates, may offer insights into development therapeutic strategies

Язык: Английский

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Structural studies of amyloid-β peptides: Unlocking the mechanism of aggregation and the associated toxicity

Biochimie, Год журнала: 2017, Номер 140, С. 176 - 192

Опубликована: Июль 25, 2017

Язык: Английский

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