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,... more
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.
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FFQ are commonly used to examine the association between diet and disease. They are the most practical method for usual dietary data collection as they are relatively inexpensive and easy to administer. In Australia, the Cancer Council of... more
FFQ are commonly used to examine the association between diet and disease. They are the most practical method for usual dietary data collection as they are relatively inexpensive and easy to administer. In Australia, the Cancer Council of Victoria FFQ (CCVFFQ) version 2 and the online Commonwealth Scientific and Industrial Research Organisation FFQ (CSIROFFQ) are used. The aim of our study was to establish the level of agreement between nutrient intakes captured using the online CSIROFFQ and the paper-based CCVFFQ. The CCVFFQ and the online CSIROFFQ were completed by 136 healthy participants. FFQ responses were analysed to give g per d intake of a range of nutrients. Agreement between twenty-six nutrient intakes common to both FFQ was measured by a variety of methods. Nutrient intake levels that were significantly correlated between the two FFQ were carbohydrates, total fat, Na and MUFA. When assessing ranking of nutrients into quintiles, on average, 56 % of the participants (for al...
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There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer's disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track... more
There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer's disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the stu...
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Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as... more
Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer's disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg2 + and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p = 0.003) and AD (p = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p = 0.002) group and 0.856 for the AD (p = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD.
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The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young... more
The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks,...
Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to... more
Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
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... The Medicinal Metallochemistry of Alzheimer's Disease Robert A. Cherny1,*, Colin L. Masters1 and Ashley I. Bush2 ... [43] Roher, AE; Chaney, MO; Kuo, YM; Webster, SD; Stine, WB; Haverkamp, LJ; Woods, AS; Cotter, RJ; Tuohy, JM;... more
... The Medicinal Metallochemistry of Alzheimer's Disease Robert A. Cherny1,*, Colin L. Masters1 and Ashley I. Bush2 ... [43] Roher, AE; Chaney, MO; Kuo, YM; Webster, SD; Stine, WB; Haverkamp, LJ; Woods, AS; Cotter, RJ; Tuohy, JM; Krafft, GA; Bonnell, BS; Emmerling, MR J. Biol. ...
Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The... more
Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of an effective therapy. Here we describe the 1.8 A resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28-123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth factors, taken together with its k...
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Amyloid plaques, composed mainly of the 39-43 amino acid betaA4 peptide, are a characteristic feature of Alzheimer's disease. Generation of betaA4 by proteolytic processing of the amyloid precursor protein (APP) is thought to occur in... more
Amyloid plaques, composed mainly of the 39-43 amino acid betaA4 peptide, are a characteristic feature of Alzheimer's disease. Generation of betaA4 by proteolytic processing of the amyloid precursor protein (APP) is thought to occur in a pathway that includes the activity of two as yet unknown proteases, with beta-secretase cleaving at the N terminus and gamma-secretase releasing the C terminus of betaA4. Inhibition studies and the finding that cell surface APP can serve as a direct precursor of betaA4 suggest that the endosomal/lysosomal compartment is involved in the proteolysis of APP into betaA4. In this study we targeted APP695 chimeric proteins directly into the endosomal/lysosomal compartment. This decreased the amount of released betaA4, while the generation of the betaA4 N terminus continued. APP695 proteins were constructed also, which carried sorting signals responsible for recycling between the trans-Golgi network (TGN) and the cell surface. These proteins were proces...
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The amyloid precursor protein (APP) of Alzheimer's disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is... more
The amyloid precursor protein (APP) of Alzheimer's disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid beta peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus...
Research Interests: Caenorhabditis elegans, Drosophila melanogaster, Cell Culture, Neuronal cell death, Drosophila, and 23 moreTransition-Metal Oxides, Xenopus, Humans, Copper, Mice, Animals, The, Neurons, Lipoprotein(a), Lipid peroxidation, Xenopus laevis, Amino Acid Profile, Glycine, Species Specificity, Structure activity Relationship, Recombinant Proteins, Organometallic Compounds, Alzheimer Disease, Site-directed Mutagenesis, Oxidation-Reduction, Low Density Lipoprotein (LDL), Full Length Movies, and Amyloid Beta Precursor Protein
Research Interests: Motor neuron, Transgenic Mice, Amyotrophic Lateral Sclerosis, Mutation, Cerebral Cortex, and 14 moreMice, Animals, Spinal Cord, Medical Physiology, Gene Dosage, Superoxide Dismutase, Clinical Sciences, Neuromuscular Disorders, Biological markers, Disease Progression, Zymography, Neuromuscular, Neurosciences, and Matrix Metalloproteinase
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Research Interests: Dementia, Multidisciplinary, Down Syndrome, Amyloid, Brain, and 16 moreHumans, Female, Male, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, High Pressure Liquid Chromatography, Aged, Middle Aged, Amino Acid Profile, Molecular Mass, Molecular weight, Amino Acid Sequence, Reference Values, Alzheimer Disease, Parkinson Disease, Paired Helical Filament, and Senile Plaques
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alpha-Synuclein normally a synaptic vesicle-associated cytoplasmic protein is the major component of filamentous inclusions of neurons in... more
alpha-Synuclein normally a synaptic vesicle-associated cytoplasmic protein is the major component of filamentous inclusions of neurons in Parkinson's disease and dementia with Lewy bodies. It is also the major component of glial inclusions of multiple system atrophy. In characterizing cells derived from embryonic neural stem cells we found all oligodendrocytes had strong cytoplasmic expression of alpha-synuclein. Comparison of cells from presenilin 1 (PS1)-deficient mice with wild type revealed a 7-fold increase in oligodendrocytes. Western blotting analysis indicated the cells contained alpha-synuclein monomers and SDS-stable dimers and trimers. This cell system of oligodendroglial alpha-synuclein expression is a useful system to study alpha-synuclein metabolism in the cell type affected in multiple system atrophy. Increased oligodendroglial cell numbers from PS1-deficient cells provides further evidence for a role of PS1-dependent Notch signalling in cell fate decisions.
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Research Interests: Neurobiology Of Disease, Immunohistochemistry, Neurobiology, Gene expression, Western blotting, and 20 moreBrain, Liver, Cerebral Cortex, Mice, Female, Animals, Spinal Cord, Peripheral Nervous System, Heart, Central Nervous System, Lung, Clinical Sciences, Enteric Nervous System, Globus Pallidus, Nervous System, Sialic Acid, Amino Acid Sequence, Membrane Protein, Neurosciences, and Purkinje cell
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Mutations in the presenilin genes are associated with early onset familial Alzheimer's disease and lead to increased accumulation of beta A4 peptide, the proteolytic product of the amyloid precursor protein (APP). To test whether... more
Mutations in the presenilin genes are associated with early onset familial Alzheimer's disease and lead to increased accumulation of beta A4 peptide, the proteolytic product of the amyloid precursor protein (APP). To test whether presenilins interfere with APP metabolism, presenilin-2 (PS2) was coexpressed with APP in mammalian cells. Analysis of PS2 immunoprecipitates revealed that a fraction of APP was associated with the PS2 immunocomplexes. This non-covalent association was specific for the APP family of proteins and restricted to immature forms, occurring probably during transit through the endoplasmic reticulum. Additionally, coexpression with PS2 resulted in a decrease of APP secretion, suggesting a direct participation of presenilins in the intracellular sorting, trafficking and processing of APP molecules.