Ruthenium(II)–arene complexes with chelating quinoline ligands as anti-amyloid agents

2021 ◽  
pp. 1-7
Author(s):  
Cade J. Meiss ◽  
Paige J. Bothwell ◽  
Michael I. Webb
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ions ◽  
Amyloid Beta ◽  
The Other ◽  
Soluble Form ◽  
Aβ Peptide ◽  
Arene Complexes ◽  
Therapeutic Development ◽  
Neurotoxic Agent

Recent recognition of the soluble form of the amyloid-beta (Aβ) peptide as a neurotoxic agent in Alzheimer’s disease (AD) has spurred the development of agents to target this species. Because Aβ is known to chelate metal ions in solution, metal-based therapeutics are uniquely suited to exploit this affinity, where coordination to Aβ has been shown to impact the neurotoxicity of the peptide. Ruthenium(II)–arene complexes are unique candidates for evaluation, as one face of the molecule is blocked by the hydrophobic arene ring, while coordination to the Aβ peptide can occur on the other side of the molecule. We have prepared and evaluated two Ru(II)–arene complexes with chelating quinoline-based ligands, Ru1 and Ru2, for their respective anti-amyloid abilities. Although both complexes decreased the aggregation of soluble Aβ, Ru1 displayed promise in disrupting formed aggregates of the peptide. These findings represent an exciting new avenue for therapeutic development in AD, where both sides of the aggregation equilibrium are affected.

Molecular dynamic studies of amyloid-beta interactions with curcumin and Cu2+ ions

2015 ◽  
Vol 69 (9) ◽  
Author(s):  
Stanislav Kozmon ◽  
Igor Tvaroška
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Transition Metals ◽  
Metal Ions ◽  
Molecular Dynamic ◽  
Amyloid Beta ◽  
Md Simulations ◽  
Aβ Peptide ◽  
Dynamic Studies

AbstractAmyloid-beta (Aβ) peptide readily forms aggregates that are associated with Alzheimer’s disease. Transition metals play a key role in this process. Recently, it has been shown that curcumin (CUA), a polyphenolic phytochemical, inhibits the aggregation of Aβ peptide. However, interactions of Aβ peptide with metal ions or CUA are not entirely clear. In this work, molecular dynamics (MD) simulations were carried out to clear the nature of interactions between the 42-residue Aβ peptide (Aβ-42) and Cu

The Importance of Understanding Amylin Signaling Mechanisms for Therapeutic Development in the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 26 (12) ◽  
pp. 1345-1355 ◽  
Author(s):  
Spencer Servizi ◽  
Rachel R. Corrigan ◽  
Gemma Casadesus
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Signaling Cascades ◽  
Complex Nature ◽  
Amyloid Accumulation ◽  
Therapeutic Development ◽  
Critical Insight ◽  
The Brain

Type II Diabetes (T2D) is a major risk factor for Alzheimer’s Disease (AD). These two diseases share several pathological features, including amyloid accumulation, inflammation, oxidative stress, cell death and cognitive decline. The metabolic hormone amylin and amyloid-beta are both amyloids known to self-aggregate in T2D and AD, respectively, and are thought to be the main pathogenic entities in their respective diseases. Furthermore, studies suggest amylin’s ability to seed amyloid-beta aggregation, the activation of common signaling cascades in the pancreas and the brain, and the ability of amyloid beta to signal through amylin receptors (AMYR), at least in vitro. However, paradoxically, non-aggregating forms of amylin such as pramlintide are given to treat T2D and functional and neuroprotective benefits of amylin and pramlintide administration have been reported in AD transgenic mice. These paradoxical results beget a deeper study of the complex nature of amylin’s signaling through the several AMYR subtypes and other receptors associated with amylin effects to be able to fully understand its potential role in mediating AD development and/or prevention. The goal of this review is to provide such critical insight to begin to elucidate how the complex nature of this hormone’s signaling may explain its equally complex relationship with T2D and mechanisms of AD pathogenesis.

scholarly journals Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Somayra S. A. Mamsa ◽  
Bruno P. Meloni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Amyloid Beta ◽  
Beneficial Effects ◽  
Therapeutic Development ◽  
Therapeutic Compounds ◽  
Tau Aggregation ◽  
Excitotoxic Cell Death

A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.

scholarly journals Functional Switching of a Native Neuropeptide Through Interactions with Pathogenic Factors in Dementia

2021 ◽  
Author(s):  
Jiyeon Han ◽  
Eunju Nam ◽  
Jiwon Yoon ◽  
Tongrui Qian ◽  
Yulong Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ions ◽  
Amyloid Beta ◽  
Conformational Transition ◽  
Metal Free ◽  
Pathogenic Factors ◽  
Functional Switching

We discovered that the function of a native neuropeptide, somatostatin (SST), is switched through its conformational transition in the presence of metal ions, metal-free amyloid-beta (Abeta), and metal-bound Abeta that are associated with toxicity observed in the brains of Alzheimer’s disease patients.

scholarly journals Structural biology of Alzheimer's disease

2014 ◽  
Vol 70 (a1) ◽  
pp. C698-C698
Author(s):  
Luke Miles ◽  
Gabriela Crespi ◽  
Tracy Nero ◽  
Michael Parker
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cross Reactivity ◽  
Soluble Form ◽  
Plaque Burden ◽  
Breakdown Product ◽  
Pathological Feature ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
N Terminus

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans with age being the biggest risk factor. The mechanisms by which the disease progresses to cognitive decline in the sufferer are complex and not fully elucidated. A defining pathological feature is the deposition of extracellular plaques composed primarily of misfolded amyloid beta (Aβ) peptide: a proteolytic breakdown product of the much larger Amyloid Precursor Protein. While Aβ peptides are the main constituents of amyloid plaques that burden the diseased brain, plaque burden correlates poorly with the severity of the disease. There is accumulating evidence that a prefibrillar or protofibrillar soluble form of Aβ can compromise neuronal functions and trigger cell death. Immunotherapy targeting Abeta is a promising direction in AD research with active and passive immunotherapies shown to lower cerebral Aβ levels and rescue cognitive function in animal models. Anti-Aβ immunotherapies are a significant class of AD therapeutics currently in human clinical trials. We have been examining the molecular basis of antibody engagement of Aβ epitopes to inform the analysis of clinical trial data and to guide the engineering of anti-Aβ antibodies with optimised specificity and affinity. We have determined the structures of three different AD antibodies in complex with Ab peptides: (1) WO2, which recognises the N-terminus of Aβ, (2) Mab 2286, which like the AD immunotherapeutic Ponezumab (Pfizer), shows specificity for the C-terminus of Aβ40 but has no significant cross-reactivity with Aβ42/43, and (3) Bapineuzumab, a humanized antibody developed by Pfizer and Johnson & Johnson which recognises the N-terminus of Aβ but cannot recognize N-terminally modified or truncated Aβ peptides (1). All these studies reveal surprising aspects of Aβ peptide recognition by the antibodies and suggest new avenues for AD antibody development.

Insight into molecular interactions of Aβ peptide and gelatinase from Enterococcus faecalis: a molecular modeling approach

RSC Advances ◽  
2015 ◽  
Vol 5 (14) ◽  
pp. 10488-10496 ◽  
Author(s):  
Chidambar B. Jalkute ◽  
Sagar H. Barage ◽  
Kailas D. Sonawane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Modeling ◽  
Enterococcus Faecalis ◽  
Amyloid Beta ◽  
Molecular Interactions ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Modeling Approach ◽  
Insight Into

Alzheimer's disease is characterized by the presence of extracellular deposition of amyloid beta (Aβ) peptides.

scholarly journals Functional Switching of a Native Neuropeptide Through Interactions with Pathogenic Factors in Dementia

2021 ◽  
Author(s):  
Jiyeon Han ◽  
Eunju Nam ◽  
Jiwon Yoon ◽  
Tongrui Qian ◽  
Yulong Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ions ◽  
Amyloid Beta ◽  
Conformational Transition ◽  
Metal Free ◽  
Pathogenic Factors ◽  
Functional Switching

We discovered that the function of a native neuropeptide, somatostatin (SST), is switched through its conformational transition in the presence of metal ions, metal-free amyloid-beta (Abeta), and metal-bound Abeta that are associated with toxicity observed in the brains of Alzheimer’s disease patients.

scholarly journals Natural Products Targeting Amyloid Beta in Alzheimer’s Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2341
Author(s):  
Joo-Hee Lee ◽  
Na-Hyun Ahn ◽  
Su-Bin Choi ◽  
Youngeun Kwon ◽  
Seung-Hoon Yang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Natural Products ◽  
Amyloid Beta ◽  
Conformational Changes ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Peptide Formation ◽  
Current Clinical Trial

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.

scholarly journals Identification of amyloid beta in small extracellular vesicles via Raman spectroscopy

2021 ◽  
Author(s):  
Meruyert Imanbekova ◽  
Sorina Suarasan ◽  
Tatu Rojalin ◽  
Rachel Mizenko ◽  
Silvia Hilt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Raman Spectroscopy ◽  
Extracellular Vesicles ◽  
Amyloid Beta ◽  
Aβ Peptide

The hallmark of Alzheimer’s disease (AD) pathogenesis is believed to be the production and deposition of amyloid-beta (Aβ) peptide into extracellular plaques. Existing research indicates that extracellular vesicles (EVs) can...

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