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ABSTRACT: 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.
Inorganic Chemistry 03/2013; · 4.60 Impact Factor
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Alan Rembach,
Noel G Faux,
Andrew D Watt,
Kelly K Pertile,
Rebecca L Rumble,
Brett O Trounson,
Christopher J Fowler,
Blaine R Roberts,
Keyla A Perez,
Qiao-Xin Li, [......], Kevin J Barnham,
Kathryn A Ellis,
Cassandra Szoeke,
Lance Macaulay,
Christopher C Rowe,
Victor L Villemagne,
David Ames,
Ralph N Martins,
Ashley I Bush,
Colin L Masters
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ABSTRACT: BACKGROUND: A practical biomarker is required to facilitate the preclinical diagnosis of Alzheimer's disease (AD). METHODS: Plasma amyloid beta (Aβ)1-40, Aβ1-42, Aβn-40, and Aβn-42 peptides were measured at baseline and after 18 months in 771 participants from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging. Aβ peptide levels were compared with clinical pathology, neuroimaging and neuropsychological measurements. RESULTS: Although inflammatory and renal function covariates influenced plasma Aβ levels significantly, a decrease in Aβ1-42/Aβ1-40 was observed in patients with AD, and was also inversely correlated with neocortical amyloid burden. During the 18 months, plasma Aβ1-42 decreased in subjects with mild cognitive impairment (MCI) and in those transitioning from healthy to MCI. CONCLUSION: Our findings are consistent with a number of published plasma Aβ studies and, although the prognostic value of individual measures in any given subject is limited, the diagnostic contribution of plasma Aβ may demonstrate utility when combined with a panel of peripheral biomarkers.
Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2013; · 5.90 Impact Factor
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Vijaya B Kenche,
Lin W Hung,
Keyla Perez,
Irene Volitakes,
Guiseppe Ciccotosto,
Jeffrey Kwok,
Nicole Critch,
Nikki Sherratt,
Mikhalina Cortes,
Varsha Lal,
Colin L Masters,
Kazuma Murakami,
Roberto Cappai,
Paul A Adlard, Kevin J Barnham
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ABSTRACT: Brainwash! A platinum complex was developed that could be administered orally and reduce the amyloid burden in the brains of transgenic mouse models suffering from Alzheimer's disease. Analyses of brain tissues showed that treatment with the Pt compound led to a 26 % decrease in the number of amyloid β-peptide plaques.
Angewandte Chemie International Edition 02/2013; · 13.45 Impact Factor
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Andrew D Watt,
Keyla A Perez,
Alan Rembach,
Nicki A Sherrat,
Lin Wai Hung,
Timothy Johanssen,
Catriona A McLean,
Woan Mei Kok,
Craig A Hutton,
Michelle Fodero-Tavoletti,
Colin L Masters,
Victor L Villemagne, Kevin J Barnham
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ABSTRACT: The formation of low-order oligomers of β-amyloid (Aβ) within the brain is widely believed to be a central component of Alzheimer's disease (AD) pathogenesis. However, despite advances in high-throughput and high-resolution techniques such as xMAP and mass spectrometry (MS), investigations into these oligomeric species have remained reliant on low-resolution Western blots and enzyme-linked immunosorbent assays. The current investigation compared Aβ profiles within human cortical tissue using sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced laser desorption/ionization time-of-flight MS and found that whilst there was significant correlation across the techniques regarding levels of monomeric Aβ, only SDS-PAGE was capable of detecting dimeric isoforms of Aβ. The addition of synthetic di-tyrosine cross-linked Aβ(1-40)Met(35)(O) to the AD tissue demonstrated that the MS methodology was capable of observing dimeric Aβ at femto-molar concentrations, with no noticeable effect on monomeric Aβ levels. Focus turned to the association between SDS-PAGE and levels of observable dimeric Aβ within the AD brain tissue. These investigations revealed that increased levels of dimeric Aβ were observed with increasing concentrations of SDS in the sample buffer. This finding was subsequently confirmed using synthetic Aβ(1-42) and suggests that SDS was inducing the formation of dimeric Aβ. The findings that SDS promotes Aβ dimerization have significant implications for the putative role of low-order oligomers in AD pathogenesis and draw into question the utility of oligomeric Aβ as a therapeutic target.
Acta Neuropathologica 01/2013; · 9.32 Impact Factor
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Gawain McColl,
Blaine R Roberts,
Tara L Pukala,
Vijaya B Kenche,
Christine M Roberts,
Christopher D Link,
Timothy M Ryan,
Colin L Masters, Kevin J Barnham,
Ashley I Bush,
Robert A Cherny
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ABSTRACT: BACKGROUND: The 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. RESULTS: We 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. CONCLUSION: This 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.
Molecular Neurodegeneration 11/2012; 7(1):57. · 4.28 Impact Factor
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ABSTRACT: Currently, therapeutics that modify Alzheimer's disease (AD)are not available. Increasing age is the primary risk factor for AD and due to an aging global population the urgent need for effective therapeutics increases every year. This Account presents the development of an AD treatment strategy that incorporates diverse compounds with a common characteristic: the ability to redistribute metal ions within the brain. Central to cognitive decline in AD is the amyloid-β peptide (Aβ) that accumulates in the AD brain. A range of therapeutic strategies have been developed based on the premise that decreasing the brain Aβ burden will attenuate the severity of the disease symptoms. Unfortunately these treatments have failed to show any positive outcomes in large-scale clinical trials, raising many questions regarding whether therapeutics for AD can rely solely on decreasing Aβ levels. An alternate strategy is to target the interaction between Aβ and metal ions using compounds with the potential to redistribute metal ions within the brain. The original rationale for this strategy came from studies showing that metal ions promote Aβ toxicity and aggregation. In initial studies using the prototype metal-chelating compound clioquinol (CQ), CQ prevented Aβ toxicity in vitro, out-competed Aβ for metal ions without affecting the activity of metal-dependent enzymes, and attenuated the rate of cognitive decline in AD subjects in a small phase II clinical trial. All these outcomes were consistent with the original hypothesized mechanism of action for CQ where prevention or reversal of the extracellular Aβ-metal interactions could prevent Aβ toxicity. Soon after the completion of these studies, a new body of work began to suggest that this hypothesized mechanism of action for CQ was simplistic and that other factors were also important for the positive therapeutic outcomes. Perhaps most significantly, it was shown that after CQ sequesters metal ions the neutral CQ-metal complex crosses cell membranes to increase intracellular levels of the metals, thereby initiating protective cell signaling cascades. The activity of CQ therefore appeared to be two-fold: it prevented toxic interactions between Aβ and metal ions outside the cell, and it redistributed the metal ions into the cell to promote healthy cell function. To determine the significance of redistributing metal ions into the cell, glyoxalbis(N(4)-methylthiosemicarbazonato)Cu(II) [Cu(II)(gtsm)] was tested in models of AD. Cu(II)(gtsm) delivers Cu into cells, but, unlike CQ, it cannot out-compete Aβ for metal ions. When tested in AD model mice, the Cu(II)(gtsm) treatment restored cognitive function back to levels expected for cognitively healthy mice. The most advanced compound from this therapeutic strategy, PBT2, can sequester metal ions from Aβ and redistribute them into the cell like CQ. PBT2 improved cognition in a phase II clinical trial with AD patients, and further clinical testing is currently underway.
Accounts of Chemical Research 06/2012; 45(9):1604-11. · 21.64 Impact Factor
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ABSTRACT: Over the past 100 years, there has been an exponential increase in our understanding of the underlying pathology of Alzheimer's disease (AD). This growth in knowledge has largely stemmed from the intensification of research into AD which has occurred over the past three decades and the incorporation of the amyloid cascade hypothesis as the generally accepted dogma of AD pathogenesis. While at times contentious, the notion that AD arises from aberrations in amyloid-β (Aβ) production and degradation has led to a number of significant breakthroughs in the way in which AD is currently diagnosed and in the attempts at disease modifying therapies, from investigations into the underlying factors mediating the aggregation of Aβ to the development of therapeutic strategies and measures of neuroimaging allowing Aβ burden to be monitored within the AD-affected brain. This review focuses on some of the recent work we have conducted toward elucidating the role of Aβ in AD.
Journal of Alzheimer's disease: JAD 06/2012; · 3.74 Impact Factor
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ABSTRACT: One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the APP-derived amyloid β peptide (Aβ) in the brain. Altered copper homeostasis has also been reported in AD patients and is thought to increase oxidative stress and to contribute to toxic Aβ accumulation and regulate APP metabolism. The potential involvement of the N-terminal APP copper binding domain (CuBD) in these events has not been investigated. Based on the tertiary structure of the APP CuBD, we examined the histidine residues of the copper binding site (His(147), His(149), and His(151)). We report that histidines 149 and 151 are crucial for CuBD stability and APP metabolism. Co-mutation of the APP CuBD His(149) and His(151) to asparagine decreased APP proteolytic processing, impaired APP endoplasmic reticulum-to-Golgi trafficking, and promoted aberrant APP oligomerization in HEK293 cells. Expression of the triple H147N/H149N/H151N-APP mutant led to up-regulation of the unfolded protein response. Using recombinant protein encompassing the APP CuBD, we found that insertion of asparagines at positions 149 and 151 altered the secondary structure of the domain. This study identifies two APP CuBD residues that are crucial for APP metabolism and suggests an additional role of this domain in APP folding and stability besides its previously identified copper binding activity. These findings are of major significance for the design of novel AD therapeutic drugs targeting this APP domain.
Journal of Biological Chemistry 06/2012; 287(32):26840-53. · 4.77 Impact Factor
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ABSTRACT: α-Synuclein (αS) is a small natively unfolded protein whose interactions with Cu2+ have been proposed to play a role in Parkinson’s disease (PD). We recently studied the Cu2+ coordination of recombinant human αS using electron paramagnetic resonance spectroscopy and identified two coordination modes
at physiological pH, one anchored upon the amino terminus (mode 1) and the other anchored upon the side chain of His50 (mode
2). Here we report the Cu2+ coordination of the A30P, E46K and A53T mutants associated with inherited forms of PD. At physiological pH, the same two
Cu2+ coordination modes were adopted by each of the familial mutants. The spectrum of Cu2+/αS(A53T) was very similar to the spectrum of the native Cu2+/αS complex; however, mode 2 coordination was marginally higher in the spectrum of Cu2+/αS(E46K) and considerably more favored in the Cu2+/αS(A30P) complex. The alteration in only the relative proportion of modes 1 and 2 suggests the familial mutations introduce
structural changes of the protein backbone that indirectly affect the stability, but not the identity, of the native Cu2+ coordination modes.
Applied Magnetic Resonance 05/2012; 36(2):223-229. · 0.75 Impact Factor
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ABSTRACT: In 1906, Alois Alzheimer first characterized the disease that bears his name. Despite intensive research, which has led to a better understanding of the pathology, there is no effective treatment for this disease. Of the drugs approved by the US FDA, none are disease modifying, only symptomatic. Unfortunately, there have been a number of failed clinical trials in the past 10 years where studies show either no cognitive improvement or, worse, serious side effects associated with treatment. Hence, there is a need for the field to look at alternative approaches to therapy. In this review, we will discuss how metal dyshomeostasis occurs in aging and Alzheimer's disease. Concomitantly, we will discuss how targeting this dyshomeostasis offers an effective and novel therapeutic approach. Thus far, compounds that mediate these effects have shown great potential in both preclinical animal studies as well as in early-stage clinical trials.
Future medicinal chemistry 05/2012; 4(8):955-69. · 2.52 Impact Factor
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ABSTRACT: The accumulation of senile plaques composed primarily of aggregated amyloid β-peptide (Aβ), is the major characteristic of
Alzheimer’s disease. Many studies correlate plaque accumulation and the presence of metal ions, particularly copper and zinc.
The metal binding sites of the amyloid Aβ peptide of Alzheimer’s disease are located in the N-terminal region of the full-length
peptide. In this work, the interactions with metals of a model peptide comprising the first 16 amino acid residues of the
amyloid Aβ peptide, Aβ(1–16), were studied. The effect of Cu2+ and Zn2+ binding to Aβ(1–16) on peptide structure and oligomerisation are reported. The results of ESI-MS, gel filtration chromatography
and NMR spectroscopy demonstrated formation of oligomeric complexes of the peptide in the presence of the metal ions and revealed
the stoichiometry of Cu2+ and Zn2+ binding to Aβ(1–16), with Cu2+ showing a higher affinity for binding the peptide than Zn2+.
International Journal of Peptide Research and Therapeutics 04/2012; 12(2):153-164. · 0.99 Impact Factor
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ABSTRACT: Metal-catalyzed oxidation (MCO) can lead to damage of bio-molecules and is implicated in neurodegenerative diseases, such
as Alzheimer's disease (AD). The amino acid residues, tyrosine, histidine and methionine, have been proposed to play important
roles in metal mediated oxidative stress and subsequent reactions of amyloid β peptide (Aβ) a major contributor in the pathogenesis
of AD. The MCO of Aβ residues, particularly histidine, methionine and tyrosine, and reviewed. MCO of Aβ histidine and tyrosine
residues can facilitate oligomerization and may play a role in both amyloid formation and Aβ neurotoxicity. Further work is
needed to determine the importance of Aβ oxidation in AD and the role of Aβ oxidation products and oxidative stress in disease
progression. The mechanisms of Aβ MCO are complex and multiple reaction products can form. Further study is needed to determine
the mechanisms by which Aβ MCO occursin vivo. In addition, new analytical methods are required to monitor the formation of Aβ MCO products formed during AD. The copper-H2O2 redox system provides a chemical model by which Aβ MCO can be studiedin vitro and can be used to produce oxidatively modified amino acid residues for use as standards in developing new analytical methods
to monitor Aβ MCO.
Letters in Peptide Science 04/2012; 10(5):405-412.
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Lin W Hung,
Victor L Villemagne,
Lesley Cheng,
Nicki A Sherratt,
Scott Ayton,
Anthony R White,
Peter J Crouch,
SinChun Lim,
Su Ling Leong,
Simon Wilkins, [......],
Colin L Masters,
Ashley I Bush,
Graeme O'Keefe,
Janetta G Culvenor,
Roberto Cappai,
Robert A Cherny,
Paul S Donnelly,
Andrew F Hill,
David I Finkelstein, Kevin J Barnham
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ABSTRACT: Parkinson's disease (PD) is a progressive, chronic disease characterized by dyskinesia, rigidity, instability, and tremors. The disease is defined by the presence of Lewy bodies, which primarily consist of aggregated α-synuclein protein, and is accompanied by the loss of monoaminergic neurons. Current therapeutic strategies only give symptomatic relief of motor impairment and do not address the underlying neurodegeneration. Hence, we have identified Cu(II)(atsm) as a potential therapeutic for PD. Drug administration to four different animal models of PD resulted in improved motor and cognition function, rescued nigral cell loss, and improved dopamine metabolism. In vitro, this compound is able to inhibit the effects of peroxynitrite-driven toxicity, including the formation of nitrated α-synuclein oligomers. Our results show that Cu(II)(atsm) is effective in reversing parkinsonian defects in animal models and has the potential to be a successful treatment of PD.
Journal of Experimental Medicine 04/2012; 209(4):837-54. · 13.85 Impact Factor
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ABSTRACT: Effective therapeutic interventions for Alzheimer's disease (AD) will require treatment regimes to move toward the earliest stages of the disease. For this to occur the field has to identify biomarkers that are able to accurately identify individuals at risk for progression toward AD in the presymptomatic stage. One very significant implication is that some form of population-based screening will need to be undertaken in order to identify those at risk. To date, efforts in neuroimaging brain amyloid-β (Aβ) and changes in cerebrospinal fluid Aβ and tau levels shows promise, however, it is questionable as to whether these methods are applicable for screening the general population. The Aβ peptide is also found in blood which is the most economical and efficient biological fluid to analyze. Unfortunately, investigations into blood-based diagnostic markers have produced mixed results. This variability is likely to be the result of differences in the preanalytical processing of samples and as such is delaying progress in the field. Reported preanalytical processing techniques from 87 recent articles focusing on the measurement of Aβ in blood were compared, to investigate whether basic sample-handling techniques were comparable between studies. This comparison revealed that not only is it likely that some of the variability in blood-based results is attributable to discrepancies in preanalytical methodologies but also that the field is failing to adequately report sample processing techniques. This review highlights the current shortcomings in methodological reporting and recommends a standardized blood collection methodology based on the limited consensus of the reviewed articles.
Journal of Alzheimer's disease: JAD 03/2012; 30(2):323-36. · 3.74 Impact Factor
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Cynthia P W Soon,
Paul S Donnelly,
Bradley J Turner,
Lin W Hung,
Peter J Crouch,
Nicki A Sherratt,
Jiang-Li Tan,
Nastasia K-H Lim,
Linh Lam,
Laura Bica, [......],
James L Hickey,
Julia Morizzi,
Andrew Powell,
David I Finkelstein,
Janetta G Culvenor,
Colin L Masters,
James Duce,
Anthony R White, Kevin J Barnham,
Qiao-Xin Li
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
Journal of Biological Chemistry 12/2011; 286(51):44035-44. · 4.77 Impact Factor
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Cynthia P.W. Soon,
Paul S. Donnelly,
Bradley J. Turner,
Lin W. Hung,
Peter J. Crouch,
Nicki A. Sherratt,
Jiang-Li Tan,
Nastasia K-H. Lim,
Linh Lam,
Laura Bica, [......],
James L. Hickey,
Julia Morizzi,
Andrew Powell,
David I. Finkelstein,
Janetta G. Culvenor,
Colin L. Masters,
James Duce,
Anthony R. White, Kevin J. Barnham,
Qiao-Xin Li
[show abstract]
[hide abstract]
ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor
neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato)
copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier permeable complex. In vitro the compound inhibits
the action of peroxynitrite on Cu,Zn superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment
of transgenic SOD1G93A mice with CuII(atsm) at pre-symptomatic and symptomatic ages was performed. The mice were examined
for improvement in life span and motor function, as well as histological and biochemical changes to key disease markers. Systemic
treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic
animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as
well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons, and attenuated
astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated
and fragmented TAR DNA-binding protein 43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm)
therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons
with therapeutic potential for ALS.
Journal of Biological Chemistry 10/2011; · 4.77 Impact Factor
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Peter J Crouch,
Maria S Savva,
Lin W Hung,
Paul S Donnelly,
Alexandra I Mot,
Sarah J Parker,
Mark A Greenough,
Irene Volitakis,
Paul A Adlard,
Robert A Cherny,
Colin L Masters,
Ashley I Bush, Kevin J Barnham,
Anthony R White
[show abstract]
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ABSTRACT: Impaired metal ion homeostasis causes synaptic dysfunction and treatments for Alzheimer's disease (AD) that target metal ions have therefore been developed. The leading compound in this class of therapeutic, PBT2, improved cognition in a clinical trial with AD patients. The aim of the present study was to examine the cellular mechanism of action for PBT2. We show PBT2 induces inhibitory phosphorylation of the α- and β-isoforms of glycogen synthase kinase 3 and that this activity is dependent on PBT2 translocating extracellular Zn and Cu into cells. This activity is supported when Aβ:Zn aggregates are the source of extracellular Zn and adding PBT2 to Aβ:Zn preparations promotes Aβ degradation by matrix metalloprotease 2. PBT2-induced glycogen synthase kinase 3 phosphorylation appears to involve inhibition of the phosphatase calcineurin. Consistent with this, PBT2 increased phosphorylation of other calcineurin substrates, including cAMP response element binding protein and Ca²⁺/calmodulin-dependent protein kinase. These data demonstrate PBT2 can decrease Aβ levels by sequestering the Zn that promotes extracellular formation of protease resistant Aβ:Zn aggregates, and that subsequent intracellular translocation of the Zn by PBT2 induces cellular responses with synapto-trophic potential. Intracellular translocation of Zn and Cu via the metal chaperone activity of PBT2 may be an important mechanism by which PBT2 improves cognitive function in people with AD.
Journal of Neurochemistry 07/2011; 119(1):220-30. · 4.06 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. Within the brain, senile plaques, which comprise extracellular deposits of the amyloid-β peptide (Aβ), are the most common pathological feature of AD. A high concentration of Cu(2+) is found within these plaques, which are also areas under oxidative stress. Laboratory work has shown that in vitro Aβ will react with Cu(2+) to induce peptide aggregation and the production of reactive oxygen species. As such, this interaction offers a possible explanation for two of the defining pathological features observed in the AD brain: the presence of amyloid plaques, which consist largely of insoluble Aβ aggregates, and the abundant oxidative stress therein. Researchers have accordingly put forth the "metals hypothesis" of AD, which postulates that compounds designed to inhibit Cu(2+)/Aβ interactions and redistribute Cu(2+) may offer therapeutic potential for treating AD. Characterization of the pH-dependent Cu(2+) coordination of Aβ is fundamental to understanding the neurological relevance of Cu(2+)/Aβ interactions and aiding the design of new therapeutic agents. In an effort to shed light on the problem, many experimental and theoretical techniques, using a variety of model systems, have been undertaken. The preceding decade has seen numerous conflicting spectroscopic reports concerning the nature of the Cu(2+)/Aβ coordination. As the number of studies has grown, the nature of the pH-dependent ligand environment surrounding the Cu(2+) cation has remained a point of contention. In large part, the difficulties can be attributed to inappropriate choices of the model system or to methods that are incapable of quantitatively delineating the presence and identity of multiple Cu(2+) coordination modes. Electron paramagnetic resonance (EPR) is the method of choice for studying paramagnetic metal-protein interactions. With the introduction of site-specific (15)N, (17)O, and (13)C isotopic labels and the application of advanced techniques, EPR is capable of eliminating much of the ambiguity. Recent EPR studies have produced the most definitive picture of the pH-dependent Cu(2+) coordination modes of Aβ and enabled researchers to address the inconsistencies present in the literature. In this Account, we begin by briefly introducing the evidence for a role of Cu(2+) in AD as well as the potential physiological and therapeutic implications of that role. We then outline the EPR methodology used to resolve the molecular details of the Cu(2+)/Aβ interactions. No drugs are currently available for altering the course of AD, and existing therapies only offer short-term symptomatic relief. This focused picture of the role of Cu(2+) in AD-related plaques offers welcome potential for the development of new methods to combat this devastating disease.
Accounts of Chemical Research 06/2011; 44(11):1146-55. · 21.64 Impact Factor
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ABSTRACT: Whilst the amyloid-β (Aβ) hypothesis/centric theory continues to evolve, genetic, biochemical and pathological evidence still suggests that Aβ is central to the etiology of Alzheimer's disease (AD). In particular, Aβ-oligomers/soluble Aβ, may be an earlier determinant of Alzheimer's disease and better correlative of cognitive impairment. Whilst there are a number of Aβ-oligomeric species in existence (making therapeutic and diagnostic biomarker choice cumbersome), their existence is in equilibrium with Aβ-fibrils, the main constituent of cored plaques. Although Alzheimer's disease remains incurable, improvements to Aβ immunotherapies and strategies to target Aβ continue to evolve, with the reliance upon Aβ imaging to shed light on the outcome of therapeutics proving very useful.
The international journal of biochemistry & cell biology 05/2011; 43(9):1247-51. · 4.89 Impact Factor
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Michelle T Fodero-Tavoletti,
Nobuyuki Okamura,
Shozo Furumoto,
Rachel S Mulligan,
Andrea R Connor,
Catriona A McLean,
Diana Cao,
Angela Rigopoulos,
Glenn A Cartwright,
Graeme O'Keefe,
Sylvia Gong,
Paul A Adlard, Kevin J Barnham,
Christopher C Rowe,
Colin L Masters,
Yukitsuka Kudo,
Roberto Cappai,
Kazuhiko Yanai,
Victor L Villemagne
[show abstract]
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ABSTRACT: While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.
Brain 03/2011; 134(Pt 4):1089-100. · 9.46 Impact Factor
