A5045915090- Alzheimer's disease research and treatments
- Trace Elements in Health
- Amyotrophic Lateral Sclerosis Research
- Prion Diseases and Protein Misfolding
- Neuroinflammation and Neurodegeneration Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Neurogenetic and Muscular Disorders Research
- Heavy Metal Exposure and Toxicity
- Neurological diseases and metabolism
- Cholinesterase and Neurodegenerative Diseases
- Crystallography and molecular interactions
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Antibiotics Pharmacokinetics and Efficacy
- Metal complexes synthesis and properties
- Antibiotic Resistance in Bacteria
- Aluminum toxicity and tolerance in plants and animals
- Air Quality and Health Impacts
- Lysosomal Storage Disorders Research
- Olfactory and Sensory Function Studies
- Mitochondrial Function and Pathology
- Immune cells in cancer
- Nuclear Receptors and Signaling
QIMR Berghofer Medical Research Institute
2017-2025
The University of Queensland
2022-2025
Queensland University of Technology
2023-2025
University of Eastern Finland
2016-2024
The University of Melbourne
2012-2022
University of Rhode Island
2022
Vanderbilt University Medical Center
2021
Florey Institute of Neuroscience and Mental Health
2003-2017
Mental Health Research Institute
2004-2016
In-Q-Tel
2011-2014
Abstract The copper compound Cu II (atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). is neuroprotective in mutant SOD1 mouse models ALS where its activity ascribed part improving availability essential copper. However, mutations cause only ~ 2% cases and therapeutic relevance sporadic unresolved. Herein we assessed spinal cord tissue from human copper-related changes. We found that when compared control natural...
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...
A major source of free radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. The Alzheimer's disease amyloid precursor protein (APP) is a regulator neuronal copper homeostasis. APP knockout mice elevated levels cerebral cortex, whereas APP-overexpressing transgenic reduced levels. Importantly, binding to can greatly reduce औ vitro. understand this interaction at molecular level we solved structure...
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...
Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. damage could result from interactions between highly reactive transition metals copper (Cu) endogenous reducing and/or oxidizing molecules brain. One molecule, homocysteine, a thiol‐containing amino acid, has previously been shown to modulate Cu toxicity HeLa endothelial cells vitro . Due possible link hyperhomocysteinemia AD, we examined whether...
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...
The amyloid precursor protein (APP) of Alzheimer's disease can reduce copper (II) to (I) in a cell-free system potentially leading increased oxidative stress neurons. We used neuronal cultures derived from APP knock-out (APP(-/-)) and wild-type (WT) mice examine the role neurotoxicity. WT cortical, cerebellar, hippocampal neurons were significantly more susceptible than their respective APP(-/-) toxicity induced by physiological concentrations but not zinc or iron. There was no difference...
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....
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...
Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) humans and an expression level-dependent phenotype transgenic rodents. We show that oral treatment with therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper<sup>II</sup> [Cu<sup>II</sup>(atsm)] increased concentration of mutant SOD1 (SOD1G37R) ALS model mice, but paradoxically improved locomotor function survival mice. To determine why mice levels had phenotype, we...
Arginase, expressed in endothelial cells and upregulated aging blood vessels, competes with NO synthase (NOS) for l -arginine, thus modulating vasoreactivity attenuating signaling. Moreover, arginase inhibition restores NOS signaling -arginine responsiveness old rat aorta. The isoform responsible NOS, however, remains unknown. Because isoform-specific inhibitors are unavailable, we used an antisense (AS) oligonucleotide approach to knockdown I (Arg I). Western blot quantitative PCR confirmed...
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...
Oxidized low-density lipoprotein (OxLDL) impairs NO signaling and endothelial function, contributes to the pathogenesis of atherosclerosis. Arginase reciprocally regulates levels in cells by competing with synthase for substrate l-arginine. In human aortic cells, OxLDL stimulation increased arginase enzyme activity a time- dose-dependent manner. reached its maximum as early 5 minutes, was maintained period more than 48 hours, associated reciprocal decrease metabolite (NOx [nitrite nitrate])...
Parkinson’s disease (PD) is a progressive, chronic characterized by dyskinesia, rigidity, instability, and tremors. The defined the presence of Lewy bodies, which primarily consist aggregated α-synuclein protein, accompanied loss monoaminergic neurons. Current therapeutic strategies only give symptomatic relief motor impairment do not address underlying neurodegeneration. Hence, we have identified CuII(atsm) as potential for PD. Drug administration to four different animal models PD resulted...