A5006373060- Trace Elements in Health
- Alzheimer's disease research and treatments
- Heavy Metal Exposure and Toxicity
- Parkinson's Disease Mechanisms and Treatments
- Aluminum toxicity and tolerance in plants and animals
- Cholinesterase and Neurodegenerative Diseases
- Drug Transport and Resistance Mechanisms
- Neurological diseases and metabolism
- Mitochondrial Function and Pathology
- Dementia and Cognitive Impairment Research
- Prion Diseases and Protein Misfolding
- Genetic Neurodegenerative Diseases
- Amyotrophic Lateral Sclerosis Research
- Lysosomal Storage Disorders Research
- Neurological disorders and treatments
- Nuclear Receptors and Signaling
- Metal complexes synthesis and properties
- Computational Drug Discovery Methods
- Metabolomics and Mass Spectrometry Studies
- Pharmacological Effects and Toxicity Studies
- Neuroscience and Neuropharmacology Research
- Nanocluster Synthesis and Applications
- Cardiac, Anesthesia and Surgical Outcomes
- S100 Proteins and Annexins
- RNA regulation and disease
The University of Melbourne
2014-2024
Florey Institute of Neuroscience and Mental Health
2015-2024
In-Q-Tel
2013-2016
Mental Health Research Institute
2005-2014
Parks Victoria
2014
CSIRO Health and Biosecurity
2006
Monash University
2001
Background: Alzheimer disease (AD) may be caused by the toxic accumulation of -amyloid (A).Objective: To test this theory, we developed a clinical intervention using clioquinol, metal-proteinattenuating compound (MPAC) that inhibits zinc and copper ions from binding to A, thereby promoting A dissolution diminishing its properties.Methods: A pilot phase 2 trial in patients with moderately severe disease.Results: Thirty-six subjects were randomized.The effect treatment was significant more...
Amyloid beta peptide (Abeta) is the major constituent of extracellular plaques and perivascular amyloid deposits, pathognomonic neuropathological lesions Alzheimer's disease. Cu(2+) Zn(2+) bind Abeta, inducing aggregation giving rise to reactive oxygen species. These reactions may play a deleterious role in disease state, because high concentrations iron, copper, zinc have been located diseased brains. Here we show that coordination metal ions Abeta same both aqueous solution lipid...
Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased oxidative stress could modulate or regulate two of key neurochemical hallmarks Alzheimer's (AD): tau phosphorylation, and ß-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die first week life, develop a complex heterogeneous phenotype arising stress. Treatment these mice catalytic...
Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (P
Aging and Alzheimer's disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it unknown whether continuous age- AD-related cortical degradation alters asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order regions exhibiting pronounced at age ~20 also asymmetry-loss across lifespan. Hence, accelerated thinning (previously) thicker homotopic hemisphere a aging. This...
Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Copper iron both show marked increases age may adversely interact the amyloid-beta (Abeta) peptide causing its aggregation production neurotoxic hydrogen peroxide (H(2)O(2)), contributing to pathogenesis AD. Amyloid precursor protein (APP) possesses copper/zinc binding sites in amino-terminal domain Abeta domain. Here we demonstrate that overexpression...
Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability several proteins have established roles in adaptation to hypoxic or oxidative stress. These include transcriptional activators HIF-1alpha HIF-2alpha. The ability inhibitors HIF stabilize involved neurons prevent neuronal injury remains unclear. We reported structurally diverse low molecular weight peptide up-regulate HIF-dependent target...
To determine whether changes in brain biometals Alzheimer disease (AD) and normal tissue are tandemly associated with amyloid beta-peptide (Abeta) burden dementia severity.The authors measured zinc, copper, iron, manganese, aluminum Abeta levels postmortem neocortical from patients AD (n = 10), age-matched control subjects 14), schizophrenia 26), 8). Severity of cognitive impairment was assessed the Clinical Dementia Rating Scale (CDR).There a significant, more than twofold, increase zinc...
The abnormal form of the prion protein (PrP) is believed to be responsible for transmissible spongiform encephalopathies. A peptide encompassing residues 106−126 human PrP (PrP106−126) neurotoxic in vitro due its adoption an amyloidogenic fibril structure. Alzheimer's disease amyloid β (Aβ) also undergoes fibrillogenesis become neurotoxic. Aβ aggregation and toxicity highly sensitive copper, zinc, or iron ions. We show that PrP106−126 aggregation, as assessed by turbidometry, abolished...
Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-beta (Abeta) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3beta (GSK3beta) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3beta. The the use copper-bis(thiosemicarbazonoto) complexes increase intracellular copper bioavailability inhibit GSK3beta through activation Akt signaling...
Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta contains high affinity metal binding site that modulates aggregation and toxicity. Therefore, identifying molecules targeting this represents valid therapeutic strategy. To test hypothesis, range of L-PtCl(2) (L = 1,10-phenanthroline derivatives) complexes were examined shown to bind Abeta, inhibit neurotoxicity rescue Abeta-induced synaptotoxicity in mouse hippocampal slices....
Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency striatal degeneration. Copper iron are increased striata HD patients, but role these metals pathogenesis unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations copper found human brain reiterated brains affected transgenic mice. Increased correlated with decreased levels export protein,...
Copper and zinc play important roles in Alzheimer disease pathology with recent reports describing potential therapeutics based on modulation of metal bioavailability. We examined the ability a range bis(thiosemicarbazonato) complexes (MII(btsc), where M=CuII or ZnII) to increase intracellular levels Chinese hamster ovary cells overexpressing amyloid precursor protein (APP-CHO) subsequent effect extracellular amyloid-beta peptide (Abeta). The CuII(btsc) were engineered be either stable both...
To understand the mechanisms of neuronal Zn2+ homeostasis better, experimental data obtained from cultured cortical neurons were used to inform a series increasingly complex computational models. Total metals (inductively coupled plasma-mass spectrometry), resting metallothionein, (65)Zn2+ uptake and release, intracellular free levels using ZnAF-2F determined before after exposed increased Zn2+, either with or without addition ionophore (pyrithione) metal chelators [EDTA, clioquinol (CQ),...
J. Neurochem. (2011) 119 , 220–230. Abstract Impaired metal ion homeostasis causes synaptic dysfunction and treatments for Alzheimer’s disease (AD) that target ions have therefore been developed. The leading compound in this class of therapeutic, PBT2, improved cognition a clinical trial with AD patients. aim the present study was to examine cellular mechanism action PBT2. We show PBT2 induces inhibitory phosphorylation α‐ β‐isoforms glycogen synthase kinase 3 activity is dependent on...
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates brains of HD patients and mouse models. However, cellular subcellular sites iron accumulation, as well significance to progression are not understood. We used independent approaches investigate location brain accumulation. In R6/2 brain, synchotron x-ray fluorescence analysis revealed accumulation discrete puncta perinuclear cytoplasm...
We recently reported that Parkinsonian and dementia phenotypes emerge between 7-12 months of age in tau-/- mice on a Bl6/129sv mixed background. These observations were partially replicated by another group using pure Bl6 background mice, but notably they did not observe cognitive phenotype. A third found impairment at 20-months age. To reconcile the observations, here we considered genetic, dietary environmental variables both studies, performed an extended set behavioral studies 12-month...
Background and Purpose Diacetyl‐bis(4‐methyl‐3‐thiosemicarbazonato)copper II (Cu (atsm)) ameliorates neurodegeneration delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Parkinson's (PD), yet the mechanism action remains uncertain. Promising results were recently reported for separate Phase 1 studies ALS patients PD patients. Affected tissue these disorders shares features elevated Fe, low glutathione increased lipid peroxidation consistent with ferroptosis, a...
Imaging of iron and dopamine by laser ablation-inductively coupled plasma-mass spectrometry reveals a risk index for parkinsonian neurodegeneration