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metal dyshomeostasis and Alzheimer's

Tao Zhang, Thomas Pauly, Luitgard Nagel-Steger
The abnormal aggregation of amyloid β (Aβ) peptides in the brain has been recognized as a central event in Alzheimer's disease (AD). Divalent metal ions such as Zn2+ have been shown to be closely involved in modulating Aβ self-association. Although the link between Zn2+ dyshomeostasis and brain Aβ deposition has been established, the effect of Zn2+ on the aggregation of Aβ is still incompletely clarified. By combining analytical ultracentrifugation (AUC), circular dichroism (CD) spectroscopy, thioflavin T (ThT) assay and atomic force microscopy (AFM) imaging, we analyzed the impact of stoichiometric Zn2+ on the aggregation process of Aβ42, the main toxic isoform of Aβ species in the brain...
February 21, 2018: International Journal of Biological Macromolecules
Asha Hiremathad, Rangappa S Keri, A Raquel Esteves, Sandra M Cardoso, Sílvia Chaves, M Amélia Santos
Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks...
February 12, 2018: European Journal of Medicinal Chemistry
Heng-Wei Hsu, Stephen C Bondy, Masashi Kitazawa
Metals are commonly found in the environment, household, and workplaces in various forms, and a significant segment of the population is routinely exposed to the trace amount of metals from variety of sources. Exposure to metals, such as aluminum, lead, iron, and copper, from environment has long been debated as a potential environmental risk factor for Alzheimer's disease (AD) for decades, yet results from in vitro, in vivo, and human population remain controversial. In the case of copper, the neurotoxic mechanism of action was classically viewed as its strong affinity to amyloid-beta (Aβ) to help its aggregation and increase oxidative stress via Fenton reaction...
February 2, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Anne Claire Kim, Sungsu Lim, Yun Kyung Kim
Amyloid and tau aggregation are implicated in manifold neurodegenerative diseases and serve as two signature pathological hallmarks in Alzheimer's disease (AD). Though aging is considered as a prominent risk factor for AD pathogenesis, substantial evidence suggests that an imbalance of essential biometal ions in the body and exposure to certain metal ions in the environment can potentially induce alterations to AD pathology. Despite their physiological importance in various intracellular processes, biometal ions, when present in excessive or deficient amounts, can serve as a mediating factor for neurotoxicity...
January 2, 2018: International Journal of Molecular Sciences
Hema S Krishnan, Vadim Bernard-Gauthier, Michael Stephen Placzek, Kenneth Dahl, Vidya Narayanaswami, Elijahu Livni, Zhen Chen, Jing Yang, Thomas Lee Collier, Chongzhao Ran, Jacob M Hooker, Steven H Liang, Neil Vasdev
Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates...
January 3, 2018: Molecular Pharmaceutics
Yong Li, Qian Jiao, Huamin Xu, Xixun Du, Limin Shi, Fengju Jia, Hong Jiang
Biometal dyshomeostasis and toxic metal accumulation are common features in many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. The neurotoxic effects of metal imbalance are generally associated with reduced enzymatic activities, elevated protein aggregation and oxidative stress in the central nervous system, in which a cascade of events lead to cell death and neurodegeneration. Although the links between biometal imbalance and neurodegenerative disorders remain elusive, a major class of endogenous proteins involved in metal transport has been receiving increasing attention over recent decades...
2017: Frontiers in Molecular Neuroscience
Michael W Beck, Jeffrey S Derrick, Jong-Min Suh, Mingeun Kim, Kyle J Korshavn, Richard A Kerr, Woo Jong Cho, Scott D Larsen, Brandon T Ruotolo, Ayyalusamy Ramamoorthy, Mi Hee Lim
Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-β (Aβ), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool's reactivities toward multiple pathological facets to various extents...
October 9, 2017: ChemMedChem
V M Andrade, M Aschner, A P Marreilha Dos Santos
Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels...
2017: Advances in Neurobiology
Leslie A Sandusky-Beltran, Bryce L Manchester, Ewan C McNay
Zinc and copper are essential trace elements. Dyshomeostasis in these two metals has been observed in Alzheimer's disease, which causes profound cognitive impairment. Insulin therapy has been shown to enhance cognitive performance; however, recent data suggest that this effect may be at least in part due to the inclusion of zinc in the insulin formulation used. Zinc plays a key role in regulation of neuronal glutamate signaling, suggesting a possible link between zinc and memory processes. Consistent with this, zinc deficiency causes cognitive impairments in children...
August 30, 2017: Behavioural Brain Research
Nady Braidy, Anne Poljak, Chris Marjo, Helen Rutlidge, Anne Rich, Bat-Erdene Jugder, Tharusha Jayasena, Nibaldo C Inestrosa, Perminder S Sachdev
The accumulation of redox-active transition metals in the brain and metal dyshomeostasis are thought to be associated with the etiology and pathogenesis of several neurodegenerative diseases, and Alzheimer's disease (AD) in particular. As well, distinct biometal imaging and role of metal uptake transporters are central to understanding AD pathogenesis and aging but remain elusive, due inappropriate detection methods. We therefore hypothesized that Octodon degus develop neuropathological abnormalities in the distribution of redox active biometals, and this effect may be due to alterations in the expression of lysosomal protein, major Fe/Cu transporters, and selected Zn transporters (ZnTs and ZIPs)...
2017: Frontiers in Aging Neuroscience
Huamin Xu, Hong Jiang, Junxia Xie
Both iron dyshomeostasis and N-methyl-D-aspartate receptors (NMDARs)-mediated neurotoxicity have been shown to have an important role in neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence proved that activation of NMDARs could promote iron overload and iron-induced neurotoxicity by enhancing iron importer divalent metal transporter 1 (DMT1)-mediated iron uptake and iron releasing from lysosome. Also, iron overload could regulate NMDARs-mediated synaptic transmission...
2017: Frontiers in Molecular Neuroscience
A Travaglia, D La Mendola
Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal development and survival, synaptic plasticity, and cognitive function. Dysregulation of BDNF signaling is involved in several neurodegenerative disorders, including Alzheimer's disease. Alteration of metal ion homeostasis is observed both in normal aging and in many neurodegenerative diseases. Interestingly, there is a significant overlap between brain areas characterized by metal ion dyshomeostasis and those where BDNF exerts its biological activity...
2017: Vitamins and Hormones
Lin Li, Shaofeng Xu, Lifei Liu, Rentian Feng, Yongxiang Gong, Xuyang Zhao, Jiang Li, Jie Cai, Nan Feng, Ling Wang, Xiaoliang Wang, Ying Peng
The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates...
2017: Journal of Alzheimer's Disease: JAD
Mattia Toni, Maria L Massimino, Agnese De Mario, Elisa Angiulli, Enzo Spisni
Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species...
2017: Frontiers in Neuroscience
Brendan Sullivan, Gregory Robison, Jenna Osborn, Martin Kay, Peter Thompson, Katherine Davis, Taisiya Zakharova, Olga Antipova, Yulia Pushkar
Fulfilling a bevy of biological roles, copper is an essential metal for healthy brain function. Cu dyshomeostasis has been demonstrated to be involved in some neurological conditions including Menkes and Alzheimer's diseases. We have previously reported localized Cu-rich aggregates in astrocytes of the subventricular zone (SVZ) in rodent brains with Cu concentrations in the hundreds of millimolar. Metallothionein, a cysteine-rich protein critical to metal homeostasis and known to participate in a variety of neuroprotective and neuroregenerative processes, was proposed as a binding protein...
April 2017: Redox Biology
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
Erika Fornasari, Lisa Marinelli, Antonio Di Stefano, Piera Eusepi, Hasan Turkez, Stefania Fulle, Ester S Di Filippo, Andrea Scarabeo, Silvia Di Nicola, Ivana Cacciatore
BACKGROUND: Medicinal chemistry methodologies are presently used to develop multifunctional molecules which 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...
2017: 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...
September 2016: Journal of Inorganic Biochemistry
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