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metal dyshomeostasis and Alzheimer's

Ann Tiiman, Jinghui Luo, Cecilia Wallin, Lisa Olsson, Joel Lindgren, Jϋri Jarvet, Roos Per, Sabrina B Sholts, Shai Rahimipour, Jan Pieter Abrahams, Amelie Eriksson Karlström, Astrid Gräslund, Sebastian K T S Wärmländer
Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, Aβ is found in various cellular locations including membranes. So far, Cu(II)/Aβ interactions and ROS generation have not been investigated in a membrane environment...
October 4, 2016: Journal of Alzheimer's Disease: JAD
Valentina Oliveri, Carmelo Sgarlata, Graziella Vecchio
Neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are multifactorial disorders related to protein aggregation, metal dyshomeostasis, and oxidative stress. To advance understanding in this area and to contribute to therapeutic development, many efforts have been directed at devising suitable agents that can target metal ions associated with relevant biomolecules such as α-synuclein. This paper presents a new cyclodextrin-8-hydroxyquinoline conjugate and discusses the properties of four cyclodextrins 3-functionalized with 8-hydroxyquinoline as copper(II) chelators and inhibitors of copper-induced synuclein aggregation...
September 6, 2016: Chemistry, An Asian Journal
Ivana Cacciatore, Erika Fornasari, Lisa Marinelli, Antonio Di Stefano, Piera Eusepi, Hasan Turkez, Stefania Fulle, Ester Sara Di Filippo, Andrea Scarabeo
BACKGROUND: Medicinal chemistry approaches are presently under investigation to develop new multifunctional drugs able to simultaneously reduce oxidative stress, excitotoxicity, metal dyshomeostasis, and neuroinflammation that characterize neuropathological conditions, such as Alzheimer's Disease. RESULTS: Memantine (MEM) derivatives 1-6 were designed and synthesized as novel multifunctional entities with antioxidant and neuroprotective capabilities to manage neurodegenerative diseases, such as Alzheimer's Disease...
June 25, 2016: Central Nervous System Agents in Medicinal Chemistry
Irina Naletova, Vincenzo G Nicoletti, Danilo Milardi, Adriana Pietropaolo, Giuseppe Grasso
The sole role of bradykinin (BK) as an inflammatory mediator is controversial, as recent data also support an anti-inflammatory role for BK in Alzheimer's disease (AD). The involvement of two different receptors (B1R and B2R) could be a key to understand this issue. However, although copper and zinc dyshomeostasis has been demonstrated to be largely involved in the development of AD, a detailed study of the interaction of BK with these two metal ions has never been addressed. In this work, we have applied mass spectrometry, circular dichroism as well as computational methods in order to assess if copper and zinc have the ability to modulate the conformation and oligomerization of BK...
August 1, 2016: Metallomics: Integrated Biometal Science
Valentina Oliveri, Graziella Vecchio
Metal dyshomeostasis has been involved in the etiology of a host of pathologies such as Wilson's, Alzheimer's, Parkinson's, Huntington's, transfusion-related iron overload diseases and cancer. Although metal chelating agents represent a necessary therapeutic strategy in metal overload diseases, long-term use of strong chelators that are not selective, can be anticipated perturbing normal physiological functions of essential metal-requiring biomolecules. In this context, the last decade has seen a growing interest in the development of molecules, referred to as "prochelators", that have little affinity for metal ions until they are activated in response to specific stimuli...
May 17, 2016: Journal of Inorganic Biochemistry
Jeffrey S Derrick, Richard A Kerr, Kyle J Korshavn, Michael J McLane, Juhye Kang, Eunju Nam, Ayyalusamy Ramamoorthy, Brandon T Ruotolo, Mi Hee Lim
The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD...
May 16, 2016: Inorganic Chemistry
Gerwyn Morris, Michael Berk
Alzheimer`s disease is a progressive neurodegenerative illness characterized by the invariant existence of β-amyloid plaques and neurofibrillary tangles. Presently approved pharmaceutical approaches offer only marginal efficacy and as yet there is no effective treatment which reverses or arrests the disease. Thus far, drugs targeting any single aspect of disease pathology have proved to be a failure or at best provided very slight clinical benefit. The consistent failure of drugs targeting aspects of the Aβ cascade has questioned the causal role of this pathway...
2016: Current Alzheimer Research
S Mckenzie-Nickson, A I Bush, K J Barnham
Pathological aggregation of endogenous proteins is a common feature of many neurodegenerative diseases. This is generally accompanied by elevated levels of oxidative stress associated with transition metal dyshomeostasis. As such, strategies targeted toward rectifying metal imbalance are increasingly becoming an attractive therapeutic option. One class of compound showing such therapeutic potential are the bis(thiosemicarbazone) metal complexes. These are small, orally bioavailable compounds capable of crossing the blood brain barrier and capable of delivering bioavailable metal intracellularly...
February 16, 2016: Current Topics in Medicinal Chemistry
Orly Weinreb, Tamar Amit, Orit Bar-Am, Moussa B H Youdim
UNLABELLED: Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology...
July 2016: British Journal of Pharmacology
Xiubo Du, Chao Wang, Qiong Liu
Alzheimer's disease is a devastating and invariably fatal neurodegenerative brain disorder with no cure. AD is characterized by two pathological protein deposits, the senile plaques composed mainly of amyloid-β (Aβ) peptide and the neurofibrillary tangles which are bundles of paired helical filaments (PHF) of protein tau. In addition, oxidative stress, disorders in signal transduction and metal ions dyshomeostasis also play significant roles in the development of AD. A large body of studies suggests that selenium (Se), either as Se-containing compounds or as selenoproteins, may be beneficial in reducing Alzheimer's pathology...
2016: Current Topics in Medicinal Chemistry
Jeffrey R Liddell
Mitochondrial impairment and metal dyshomeostasis are suggested to be associated with many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Treatments aimed at restoring metal homeostasis are highly effective in models of these diseases, and clinical trials hold promise. However, in general, the effect of these treatments on mitochondrial metal homeostasis is unclear, and the contribution of mitochondrial metal dyshomeostasis to disease pathogenesis requires further investigation...
August 2015: Neurodegenerative Disease Management
Ashwini Kumar, Chaluveelaveedu Murleedharan Nisha, Chitrangda Silakari, Isha Sharma, Kanukanti Anusha, Nityasha Gupta, Prateek Nair, Timir Tripathi, Awanish Kumar
Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline, i.e., dementia. The disease starts with mild symptoms and gradually becomes severe. AD is one of the leading causes of mortality worldwide. Several different hallmarks of the disease have been reported such as deposits of β-amyloid around neurons, hyperphosphorylated tau protein, oxidative stress, dyshomeostasis of bio-metals, low levels of acetylcholine, etc. AD is not simple to diagnose since there is no single diagnostic test for it...
January 2016: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Akiko Kochi, Hyuck Jin Lee, Sashiprabha M Vithanarachchi, Vediappen Padmini, Matthew J Allen, Mi Hee Lim
When Alzheimer's disease (AD) progresses, several pathological features arise including accumulation of misfolded protein aggregates [e.g., amyloid-β (Aβ) plaques], metal ion dyshomeostasis, and oxidative stress. These characteristics are recently suggested to be interconnected through a potential factor, metal-associated Aβ (metal-Aβ) species. The role of metal-Aβ species in AD pathogenesis remains unclear, however. To elucidate the contribution of metal-Aβ species to AD pathology, as well as to develop small molecules as chemical tools and/or theranostic (therapeutic and diagnostic) agents for this disease, curcumin (Cur), a natural product from turmeric, and its derivatives have been studied towards both metal-free and metal-induced Aβ aggregation...
2015: Current Alzheimer Research
Robert A Colvin, Barry Lai, William R Holmes, Daewoo Lee
The purpose of this study was to demonstrate how single cell quantitative and subcellular metallomics inform us about both the spatial distribution and cellular mechanisms of metal buffering and homeostasis in primary cultured neurons from embryonic rat brain, which are often used as models of human disease involving metal dyshomeostasis. The present studies utilized synchrotron radiation X-ray fluorescence (SRXRF) and focused primarily on zinc and iron, two abundant metals in neurons that have been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease...
July 2015: Metallomics: Integrated Biometal Science
Jeffrey S Derrick, Mi Hee Lim
The growing prevalence of Alzheimer's disease (AD) has warranted the development of effective therapeutic methods. Current available drugs for AD (i.e., acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists) have only offered brief symptomatic relief. Considering that the numbers affected by AD are projected to substantially rise, long-term strategies are urgently needed. The multiple series of small molecules to combat AD have been expanded, with current methods taking aim at factors, such as misfolded protein accumulation, metal ion dyshomeostasis, and oxidative stress...
April 13, 2015: Chembiochem: a European Journal of Chemical Biology
Nelda A Rivera, Jan Novakofski, Hsin-Yi Weng, Amy Kelly, Damian Satterthwaite-Phillips, Marilyn O Ruiz, Nohra Mateus-Pinilla
Prion proteins (PrP(C)) are cell membrane glycoproteins that can be found in many cell types, but specially in neurons. Many studies have suggested PrP(C)'s participation in metal transport and cellular protection against stress in the central nervous system (CNS). On the other hand PrP(Sc), the misfolded isoform of PrP(C) and the pathogenic agent in transmissible spongiform encephalopathies (TSE), has been associated with brain metal dyshomeostasis in prion diseases. Thus, changes in metal concentration associated with protein misfolding and aggregation have been reported for human and animal prion diseases, as well as for other neurodegenerative disorders, such as Parkinson's and Alzheimer's disease...
2015: Prion
Timothy M Ryan, Nigel Kirby, Haydyn D T Mertens, Blaine Roberts, Kevin J Barnham, Roberto Cappai, Chi Le Lan Pham, Colin L Masters, Cyril C Curtain
Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu(2+)/Aβ, on the early three-dimensional structures of the Aβ1-40 and Cu(2+)/Aβ1-42 peptides in solution. We found that at molar ratios of 0.5 copper to peptide Aβ1-40 aggregated, while Aβ1-42 adopted a relatively monodisperse cylindrical shape, and at a ratio of 1...
March 2015: Metallomics: Integrated Biometal Science
Chiara Giacomelli, Maria Letizia Trincavelli, Cristina Satriano, Örjan Hansson, Diego La Mendola, Enrico Rizzarelli, Claudia Martini
Angiogenin (ANG), a member of the secreted ribonuclease family, is a potent angiogenesis stimulator that interacts with endothelial cells inducing a wide range of responses. Metal ions dyshomeostasis play a fundamental role in the onset of neurodegenerative diseases, in particular copper that is also involved in angiogenesis processes. It is known that vascular pathologies are present in neurodegenerative diseases and Angiogenin is down-regulated in Alzheimer and Parkinson diseases, as well as it has been found as one of the mutated genes in amyotrophic lateral sclerosis (ALS)...
March 2015: International Journal of Biochemistry & Cell Biology
An Zhou, Hongfei Wu, Jian Pan, Xuncui Wang, Jiaming Li, Zeyu Wu, Ailing Hui
Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (Aβ) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a-5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelating agents for AD treatment have been synthesized and characterized...
2015: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Nicole T Watt, Heledd H Griffiths, Nigel M Hooper
Dysregulation of neuronal zinc homeostasis plays a major role in many processes related to brain aging and neurodegenerative diseases, including Alzheimer's disease (AD). Yet, despite the critical role of zinc in neuronal function, the cellular mechanisms underpinning its homeostatic control are far from clear. We reported that the cellular prion protein (PrP(C)) is involved in the uptake of zinc into neurons. This PrP(C)-mediated zinc influx required the metal-binding octapeptide repeats in PrP(C) and the presence of the zinc permeable AMPA channel with which PrP(C) directly interacted...
2014: Frontiers in Cell and Developmental Biology
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