Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: Limitations, and current and future perspectives

Journal of Trace Elements in Medicine and Biology, Год журнала: 2021, Номер 67, С. 126779 - 126779

Опубликована: Май 15, 2021

Alzheimer's disease (AD) is the most prevalent cause of cognitive impairment and dementia worldwide. The pathobiology has been studied in form several hypotheses, ranging from oxidative stress, amyloid-beta (Aβ) aggregation, accumulation tau forming neurofibrillary tangles (NFT) through metal dysregulation homeostasis, dysfunction cholinergic system, to inflammatory autophagic mechanism. However, none these hypotheses led confirmed diagnostics or approved cure for disease. This review aimed as a basic an encyclopedic short course into metals AD discusses advances chelation strategies developments adopted treatment Since there accumulating evidence role both biometal dyshomeostasis (iron (Fe), copper (Cu), zinc (Zn)) metal-amyloid interactions that lead pathogenesis AD, this focuses on unraveling therapeutic have considered disease, aiming sequester free protein-bound ions reducing cerebral burden. Promising compounds possessing chemically modified moieties evolving multi-target ligands used anti-AD drug candidates are also covered. Several multidirectional multifaceted studies therapeutics show need improved synthesis, screening, analysis be able effectively present chelating drugs. Most limitations their physicochemical properties; some enhance redistribution ions, while others indirectly activate signaling pathways AD. process vivo still needs established design potential bi-functionally well inhibit Aβ aggregation by competing with metal-induced damage neurotoxicity may signal bright end chelation-based

Язык: Английский

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Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs

Ageing Research Reviews, Год журнала: 2023, Номер 88, С. 101960 - 101960

Опубликована: Май 22, 2023

Язык: Английский

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Fluorescent Fingerprint Identification of Protein Structural Changes and Disease-Specific Amyloid Beta Aggregates Based on a Single-Nanozyme Sensor Array

Analytical Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

The misfolding of amyloid β (Aβ) peptides into an aggregation state is a central hallmark the onset Alzheimer's disease (AD). However, conventional methods are mainly focused on detecting specific Aβ peptide, which makes it difficult to recognize multiple analytes with different topological features and unfolded states at same time. Here, we propose simple universal sensing strategy construct fluorescence sensor array by using single-nanozyme probe combined three fluorescent substrates as recognition units protein structural changes identify between assemblies. In this system, fingerprint-like patterns produced from nonspecific interactions proteins units. As result, can accurately 13 kinds their mixtures ratios. Moreover, discriminate against diverse conformational forms. Most importantly, successfully distinguishes species, even in artificial cerebrospinal fluid samples human serum samples. This work provides attractive reliable for predicting pathologically relevant clinical diagnosis AD.

Язык: Английский

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Biomolecules-derived biomaterials

Biomaterials, Год журнала: 2019, Номер 230, С. 119633 - 119633

Опубликована: Ноя. 15, 2019

Язык: Английский

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Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

RSC Advances, Год журнала: 2018, Номер 8(42), С. 23780 - 23804

Опубликована: Янв. 1, 2018

Alzheimer's disease (AD) is the most prevalent, progressive and multifaceted neurodegenerative disorder associated with cognition, memory behavioural impairments. There no approved diagnosis or cure for AD, it affects both developed developing countries causes a significant social economic burden. Extracellular senile plaques of amyloid beta (Aβ) intracellular neurofibrillary tangles phosphorylated Tau (pTau) in brain are considered to be pathophysiological hallmarks AD. In an attempt explain complexity multifactorial nature various hypotheses (Aβ aggregation, metal dyshomeostasis, oxidative stress, cholinergic dysfunction, inflammation downregulation autophagy) based on changes that occur during onset progression AD have been proposed. However, none capable independently explaining pathological conditions observed The complex has hampered identification validation effective biomarkers early development disease-modifying therapies. Nevertheless, hypothesis widely accepted closely correlated symptoms encompass all hypotheses. Therefore, ideal Similarly, formation can also serve as target design therapeutic tools via inclusive approach considers multiple pathways involved Our review article briefly introduces factors using interdependent but diverse Recent advances molecular techniques diagnostic interventions especially those advanced stages (clinical trials) development, given special consideration. addition, contributions from our laboratory selective toxicity covered. summary, we discuss aspects mechanisms underlie pathogenesis current progress possible bottlenecks drugs. Challenges future prospects include integration successful drugs treatment

Язык: Английский

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Analyzing Amyloid Beta Aggregates with a Combinatorial Fluorescent Molecular Sensor

Journal of the American Chemical Society, Год журнала: 2017, Номер 139(6), С. 2136 - 2139

Опубликована: Фев. 7, 2017

Different amyloid beta (Aβ) aggregates can be discriminated by a combinatorial fluorescent molecular sensor. The unique optical fingerprints generated the unimolecular analytical device provide simple means to differentiate among from different alloforms or through distinct pathways. sensor has also been used track dynamic changes that occur in Aβ aggregation states, which result formation of low weight oligomers, high protofibrils, and fibrils.

Язык: Английский

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Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

ACS Chemical Neuroscience, Год журнала: 2016, Номер 7(9), С. 1300 - 1310

Опубликована: Июнь 29, 2016

Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one hallmarks Alzheimer's disease (AD). The polymorphic oligomers fully grown fibrillar Aβ exhibit different levels neuronal toxicity. Moreover, aggregation presence redox-active metal ions like Cu2+ responsible for additional trait cellular toxicity induced by generation reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on naturally occurring chelating tripeptide (GHK) aggregation. It was shown employing various biophysical studies that P6 interact with prevent formation toxic forms oligomeric aggregates. Further, successfully sequestered from Aβ-Cu2+ complex maintained it redox-dormant state to ROS. inhibited membrane disruption efficiently prevented DNA damage caused complex. PC12 cells were rescued multifaceted when treated P6, amount ROS generated reduced. These attributes make potential therapeutic candidate ameliorate AD.

Язык: Английский

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A High Affinity Red Fluorescence and Colorimetric Probe for Amyloid β Aggregates

Scientific Reports, Год журнала: 2016, Номер 6(1)

Опубликована: Апрель 1, 2016

Abstract A major challenge in the Alzheimer’s disease (AD) is its timely diagnosis. Amyloid β (Aβ) aggregates have been proposed as most viable biomarker for diagnosis of AD. Here, we demonstrate hemicyanine-based benzothiazole-coumarin ( TC ) a potential probe detection highly toxic Aβ 42 through switch-on, enhanced (~30 fold) red fluorescence (E max = 654 nm) and characteristic colorimetric (light to purple) optical outputs. Interestingly, exhibits selectivity towards fibrils compared other abnormal protein aggregates. show nanomolar binding affinity K 1.72 × 10 7 M −1 also displace ThT bound due high affinity. The fibril-specific red-shift absorption spectra responsible observed output has attributed micro-environment change around from hydrophilic-like hydrophobic-like nature. site, energy changes properties upon interaction with further validated by molecular docking time dependent density functional theory studies.

Язык: Английский

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Muscarinic and nicotinic acetylcholine receptor agonists: current scenario in Alzheimer's disease therapy

Journal of Pharmacy and Pharmacology, Год журнала: 2018, Номер 70(8), С. 985 - 993

Опубликована: Апрель 16, 2018

Abstract Objectives Alzheimer's disease (AD) has become the primary cause of dementia. It shows a progressive cognitive dysfunction with degenerating neurons. Acetylcholine receptors (AChRs) propagate ability and it consists two members namely muscarinic (mAChRs) nicotinic (nAChRs). Where mAChRs is G-protein coupled receptor, (nAChRs) are ligand-gated ion channels. The conventional therapeutic regimen for AD three acetylcholinestearse inhibitors while single NMDA receptor antagonist. Researchers around globe developing new modifying existing AChRs agonists to develop lead candidates lower risk benefit ratio where benefits clearly outweigh adverse events. Key findings We have searched PubMed, MEDLINE, Google scholar, Science Direct and, Web keywords “Muscarinic/Nicotinic acetylcholine AD”. literature search included articles written in English. Scientific relevance clinical studies, basic science studies eligibility criteria referred this paper. M1 subtype α7 nAChR that responsible cognition memory these been major recent experimental targets mAChR agonist strategy. Summary last cholinergic enter phase 3 trial was EVP-6124 (Enceniclin) but withdrawn due severe gastrointestinal effects. aim present an overview efforts achievements targeting Muscarinic Nicotinic current review development better therapeutics.

Язык: Английский

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Aβ plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies

Biosensors and Bioelectronics, Год журнала: 2017, Номер 98, С. 54 - 61

Опубликована: Июнь 19, 2017

Язык: Английский

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