The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of the... more
The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of the glutamine repeat in huntingtin leads to the debilitating neurodegenerative disease, Huntington's disease. Similarly, there are a range of other disorders caused by trinucleotide repeat expansions encoding polyglutamine or polyalanine tracts. The age of onset of the polyglutamine-induced neurodegenerative diseases is usually negatively correlated with the length of expanded CAG/glutamine repeat. However, recent studies have given evidence that single amino acid repeats may also play critical roles in normal protein function and that changes in the length of single amino acid repeats is likely to play a beneficial role in evolution. This chapter will look at the prevalence, function and possible role single amino acid repeats have in evolution and other biological processes.
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Brain iron elevation is implicated in... more
Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.
Research Interests: Cognition, Magnetic Resonance Imaging, Treatment Outcome, Multidisciplinary, Brain, and 16 moreHumans, Female, Male, Iron, Risk factors, Aged, Middle Aged, Longitudinal Studies, Atrophy, Genotype, Risk Factors, Alzheimer Disease, Nature Communications, Cognition disorders, Gene Expression Regulation, and Cohort Studies
The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of the... more
The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of the glutamine repeat in huntingtin leads to the debilitating neurodegenerative disease, Huntington's disease. Similarly, there are a range of other disorders caused by trinucleotide repeat expansions encoding polyglutamine or polyalanine tracts. The age of onset of the polyglutamine-induced neurodegenerative diseases is usually negatively correlated with the length of expanded CAG/glutamine repeat. However, recent studies have given evidence that single amino acid repeats may also play critical roles in normal protein function and that changes in the length of single amino acid repeats is likely to play a beneficial role in evolution. This chapter will look at the prevalence, function and possible role single amino acid repeats have in evolution and other...
Research Interests:
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific... more
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex Cu(II)(atsm) tested for therapeutic efficacy in mice expressing SOD1(G93A) on a mixed genetic background. Oral administration of Cu(II)(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1(G93A) mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the Cu(II)(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in th...
We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying individuals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify individuals at risk of... more
We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying individuals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify individuals at risk of progression to Alzheimer disease (AD) within 54 months. We generated the blood-based signature for 585 healthy controls (HCs) and 74 participants with mild cognitive impairment (MCI) from the Australian Imaging, Biomarkers and Lifestyle Study who underwent clinical reclassification (blinded to biomarker findings) at 54-month follow-up. The individuals were split into estimated high and low NAB groups based on a cutoff of 1.5 standardized uptake value ratio. We assessed the predictive accuracy of the high and low NAB groupings based on progression to mild cognitive impairment or AD according to clinical reclassification at 54-month follow-up. Twelve percent of HCs with estimated high NAB progressed in comparison to 5% of HCs with estimated low NAB (odds ratio ...
Research Interests: Cognitive Science, Neurology, Cognition, Biomarkers, Positron Emission Tomography, and 15 moreLinear models, Brain, Humans, Female, Male, Follow-up studies, Clinical Sciences, Aged, Analysis of Variance, Odds ratio, Disease Progression, Alzheimer Disease, Neurosciences, Neuropsychological Tests, and Cognitive dysfunction
Research Interests: Molecular Evolution, Biological Sciences, Humans, Peptides, Genome, and 3 moreProteins, Codon Usage, and Codon
Journal of Alzheimer's Disease ISSN: 1387-2877 IOS Press DOI: 10.3233/JAD-2010-090249 ... Plasma Amyloid-β as a Biomarker in Alzheimer's Disease: The AIBL Study of Aging ... James K. Luia,b,*, Simon M. Lawsa,b,*, Qiao-Xin Lic,d,... more
Journal of Alzheimer's Disease ISSN: 1387-2877 IOS Press DOI: 10.3233/JAD-2010-090249 ... Plasma Amyloid-β as a Biomarker in Alzheimer's Disease: The AIBL Study of Aging ... James K. Luia,b,*, Simon M. Lawsa,b,*, Qiao-Xin Lic,d, Victor L. Villemagnec,e, David Amesf,g,
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Amyloid-β (Aβ) plays a central role in the pathogenesis of... more
Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Aβ as an AD biomarker and its relationship with Aβ
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The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. We calculated the anticholinergic load (ACL) of medications taken by participants of... more
The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults.
Research Interests: Cognitive Science, Dementia, Cognition, Aging, Mild Cognitive Impairment, and 23 moreExecutive Function, Memory, Humans, Older people, Female, Male, Acetylcholine, Clinical Sciences, Aged, Middle Aged, Analysis of Variance, Cognitive Function, Polypharmacy, Older Adult, Reference Values, Cross Sectional Studies, Alzheimer Disease, Neurosciences, Cognition disorders, Case Control Studies, Cohort Studies, Severity of Illness Index, and Neuropsychological Tests
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Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and... more
Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-β (Aβ) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aβ was fragile and prone to degradation in the AIBL samples, even when stored at -80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is prese...
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Serpins in Prokaryotes Qingwei Zhang, Ruby Law, Ashley M. Buckle, Lisa Cabrita, Sheena McGowan, James A. Irving, Noel G. Faux, Arthur M. Lesk, Stephen P. Bottomley and James C. Whisstock 1. Introduction An extensive bioinformatic analysis... more
Serpins in Prokaryotes Qingwei Zhang, Ruby Law, Ashley M. Buckle, Lisa Cabrita, Sheena McGowan, James A. Irving, Noel G. Faux, Arthur M. Lesk, Stephen P. Bottomley and James C. Whisstock 1. Introduction An extensive bioinformatic analysis of the genomic sequence ...
PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of... more
PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.
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ABSTRACT The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of... more
ABSTRACT The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of the glutamine repeat in huntingtin leads to the debilitating neurodegenerative disease, Huntington’s disease. Similarly, there are a range of other disorders caused by trinucleotide repeat expansions encoding polyglutamine or polyalanine tracts. The age of onset of the polyglutamine-induced neurodegenerative diseases is usually negatively correlated with the length of expanded CAG/glutamine repeat. However, recent studies have given evidence that single amino acid repeats may also play critical roles in normal protein function and that changes in the length of single amino acid repeats is likely to play a beneficial role in evolution. This chapter will look at the prevalence, function and possible role single amino acid repeats have in evolution and other biological processes.
Research Interests:
Plasma iron levels are decreased in... more
Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing.
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Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with... more
Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer's disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003). Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.
Research Interests: Cognitive Science, Mass Spectrometry, Biomarkers, Positron Emission Tomography, Linear models, and 16 moreHumans, Copper, Female, Male, Clinical Sciences, Aged, Middle Aged, Longitudinal Studies, Ceruloplasmin, Thiazoles, Alzheimers Disease, Alzheimer Disease, Neurosciences, Cognition disorders, aniline Compounds, and Psychiatric Status Rating Scales
Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The... more
Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Abeta as an AD biomarker and its relationship with Abeta load and to determine the effect of different assay methods on the interpretation of Abeta levels. Plasma Abeta1-40, Abeta1-42, and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Abeta levels were compared to Abeta load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Abeta1-42 and Abeta1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Abeta load. How...
Research Interests: Cognitive Science, Australia, Aging, Life Style, Risk assessment, and 16 moreBrain, Humans, Female, Male, Clinical Sciences, Aged, Biological markers, Risk Assessment, Alzheimers Disease, Cross Sectional Studies, Alzheimer Disease, Neurosciences, Enzyme Linked Immunosorbent Assay, Cohort Studies, Socioeconomic Factors, and Neuropsychological Tests
Research Interests: Structural Biology, Data Analysis, Data Management, E Science, Molecular Biophysics, and 11 moreTarget Tracking, DNA, X Rays, Protein crystallography, User interfaces, Data Collection, Proteins, Structure Elucidation, Very high throughput, High performance computer, and Protein Structure Determination
Page 1. 1 High-throughput protein structure determination using grid computing Jason W. Schmidberger1, Blair Bethwaite4, Colin Enticott4, Mark A. Bate1, Steve G. Androulakis1, Noel Faux5, Cyril F. Reboul1,2, Jennifer MN ...
Research Interests: Biochemistry, Bioinformatics, Grid Computing, Crystallography, Genomics, and 14 moreProduction, Parallel Processing, Molecular Biophysics, X Rays, Proteins, X ray diffraction, Very high throughput, Error Processing, IPDPS, Structure Refinement, X Ray Crystallography, Molecular Replacement, Structure Determination, and Protein Structure Determination
Research Interests: Protein Folding, Science, Cell Migration, Multidisciplinary, Macromolecular X-Ray Crystallography, and 15 moreCrystal structure, Animals, Vertebrates, Gram Positive Bacteria, Embryonic Development, Protein Secondary Structure Prediction, Protein Conformation, Amino Acid Sequence, Virus infection, Structural Similarity Index, Perforin, Cytotoxins, Photorhabdus, Molecular Sequence Data, and Cell Membrane
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Research Interests:
Research Interests: Catalysis, Kinetics, Macromolecular X-Ray Crystallography, Biological Sciences, Crystal structure, and 13 moreHumans, Enzyme, CHEMICAL SCIENCES, Active site, Protein Secondary Structure Prediction, Isoenzymes, Amino Acid Sequence, Glutamic Acid, Glutamate decarboxylase, Gamma-Aminobutyric Acid, Dimerization, Autoantigens, and Molecular Sequence Data
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Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally... more
Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.
Research Interests: Psychopharmacology, Schizophrenia, Australia, Mild Cognitive Impairment, Behavioral Medicine, and 17 moreFolic acid, Molecular Psychiatry, Biological Sciences, Prospective studies, Humans, Female, Male, Transferrin, Anemia, Iron, Risk factors, Aged, Middle Aged, Risk Factors, Cross Sectional Studies, Alzheimer Disease, and Hemoglobins
The Niemann–Pick type C1 disease protein, NPC1 may have a critical role in transition metal homeostasis.
Research Interests: Metallomics, Enzyme Inhibitors, Brain, Humans, Mice, and 8 moreFemale, Animals, Male, Proteins, Metals, CHEMICAL SCIENCES, Homeostasis, and Ceruloplasmin
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Over 3% of human proteins contain single amino acid repeats (repeat-containing proteins, RCPs). Many repeats (homopeptides) localize to important proteins involved in transcription, and the expansion of certain repeats, in particular... more
Over 3% of human proteins contain single amino acid repeats (repeat-containing proteins, RCPs). Many repeats (homopeptides) localize to important proteins involved in transcription, and the expansion of certain repeats, in particular poly-Q and poly-A tracts, can also lead to the development of neurological diseases. Previous studies have suggested that the homopeptide makeup is a result of the presence of G+C-rich tracts in the encoding genes and that expansion occurs via replication slippage. Here, we have performed a large-scale genomic analysis of the variation of the genes encoding RCPs in 13 species and present these data in an online database (http://repeats.med.monash.edu.au/genetic_analysis/). This resource allows rapid comparison and analysis of RCPs, homopeptides, and their underlying genetic tracts across the eukaryotic species considered. We report three major findings. First, there is a bias for a small subset of codons being reiterated within homopeptides, and there is no G+C or A+T bias relative to the organism's transcriptome. Second, single base pair transversions from the homocodon are unusually common and may represent a mechanism of reducing the rate of homopeptide mutations. Third, homopeptides that are conserved across different species lie within regions that are under stronger purifying selection in contrast to nonconserved homopeptides.