BackgroundThe definitive indicator of Alzheimer’s disease (AD) pathology is the profuse accumulation of amyloid-ß (Aß) within the brain. Various in vitro and cell-based models have been proposed for high throughput drug screening for potential therapeutic benefit in diseases of protein misfolding. Caenorhabditis elegans offers a convenient in vivo system for examination of Aß accumulation and toxicity in a complex multicellular organism. Ease of culturing and a short life cycle make this animal model well suited to rapid screening of candidate compounds.ResultsWe have generated a new transgenic strain of C. elegans that expresses full length Aß1-42. This strain differs from existing Aß models that predominantly express amino-truncated Aß3-42. The Aß1-42 is expressed in body wall muscle cells, where it oligomerizes, aggregates and results in severe, and fully penetrant, age progressive-paralysis. The in vivo accumulation of Aß1-42 also stains positive for amyloid dyes, consistent with in vivo fibril formation. The utility of this model for identification of potential protective compounds was examined using the investigational Alzheimer’s therapeutic PBT2, shown to be neuroprotective in mouse models of AD and significantly improve cognition in AD patients. We observed that treatment with PBT2 provided rapid and significant protection against the Aß-induced toxicity in C. elegans.ConclusionThis C. elegans model of full length Aß1-42 expression can now be adopted for use in screens to rapidly identify and assist in development of potential therapeutics and to study underlying toxic mechanism(s) of Aß.
Amelyoid- peptide (A) is a major causative agent responsible for Alzheimer's disease (AD). A contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl2 (L ؍ 1,10-phenanthroline derivatives) complexes were examined and shown to bind to A, inhibit neurotoxicity and rescue A-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to A altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of A. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for A onto the platinum complexes. The potent effect of the L-PtCl 2 complexes identifies this class of compounds as therapeutic agents for AD.
Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Ab peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Ab with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Ab oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Ab metal interactions, inhibiting the formation of toxic Ab species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Ab. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called 'metal protein attenuating compound' approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD.
AbbreviationsAb, amyloid-b peptide; AD, Alzheimer's disease; CQ, clioquinol; MPAC, metal protein attenuating compound; ROS, reactive oxygen species
IntroductionDementia is characterized by the loss of or decline in memory and other cognitive abilities. Alzheimer's disease (AD) (Alzheimer et al., 1995) is the most common type of dementia and accounts for an estimated 60-80% of cases. AD is an irreversible, progressive neurodegenerative disorder leading invariably to death usually within 7-10 years of diagnosis. Age is the dominant risk factor in AD, and the progressive nature of neurodegeneration ultimately leads to synaptic failure and neuronal damage (Masters and Beyreuther, 1988) in cortical areas of the brain essential for memory and higher mental functions. The increase in the number of new cases of AD is the direct consequence of an improvement in life expectancy. There are currently 18 million people worldwide with AD and this figure is projected to nearly double by 2025 to 34 million (Alzheimer's Association, 2010). In the USA alone the estimated annual cost of caring for over 5 million AD patients is $172 billion (Alzheimer's Association, 2010). Besides the monetary cost, the spouses, relatives and friends of AD patients experience emotional, physical and financial stresses during the years of caregiving that is impossible to quantify. Clearly, AD represents a major socio-economic problem which requires better assessment, management and effective therapies in order t...
8-Hydroxyquinolines (8HQ) have found widespread application in chemistry and biology due to their ability to complex a range of transition metal ions. The family of 2-substituted 8HQs has been proposed for use in the treatment of Alzheimer's disease (AD). Most notably, the therapeutic PBT2 (Prana Biotechnology Ltd.) has been shown to act as an efficient metal chaperone, disaggregate metal-enriched amyloid plaques comprised of the Aβ peptide, inhibit Cu/Aβ redox chemistry, and reverse the AD phenotype in transgenic animal models. Yet surprisingly little is known about the molecular interactions at play. In this study, we show that the homologous ligand 2-[(dimethylamino)methyl]-8-hydroxyquinoline (HL) forms a CuL complex with a conditional (apparent) dissociation constant of 0.33 nM at pH 6.9 and is capable of forming ternary Cu(2+) complexes with neurotransmitters including histamine (HA), glutamic acid (Glu), and glycine (Gly), with glutathione disulfide (GSSG), and with histidine (His) side chains of proteins and peptides including the Aβ peptide. Our findings suggest a molecular basis for the strong metal chaperone activity of PBT2, its ability to attenuate Cu(2+)/Aβ interactions, and its potential to promote neuroprotective and neuroregenerative effects.
The design of small molecules that can target the aggregation of Aβ as potential therapeutic agents for Alzheimer's disease is an area of study that has attracted a lot of attention recently. The novel ligand methyl 1-butyl-2-pyridyl-benzimidazole carboxylate was prepared for the synthesis of a series of new iridium(III), ruthenium(II), and platinum(II) 2-pyridyl-benzimidazole complexes. The crystal structure of the half-sandwich iridium(III) complex was established by X-ray diffraction. An arrangement of two cationic complexes in the unit cell is observed, and it seems to be organized by weak π···π interactions that are taking place between two symmetry-related benzimidazole ring systems. All new compounds inhibited aggregation of Aβ1-42 in vitro as shown by both thioflavin T fluorescence assay and transmission electron microscopy. Among them the Ir compound rescued the toxicity of Aβ1-42 in primary cortical neurons effectively.
Extended X-ray absorption fine structure spectroscopy, mass spectrometry, dynamic light scattering and density functional theory are combined to derive structural models for the interaction of neurotoxicity-ablating platinum-based compounds with the amyloid-β peptide.
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