A5003080475- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Trace Elements in Health
- Neuroscience and Neuropharmacology Research
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- S100 Proteins and Annexins
- Supramolecular Self-Assembly in Materials
- Drug Transport and Resistance Mechanisms
- Biochemical effects in animals
- Lipid Membrane Structure and Behavior
- Heavy Metal Exposure and Toxicity
- Parkinson's Disease Mechanisms and Treatments
- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Neuropeptides and Animal Physiology
- Antibiotic Resistance in Bacteria
- Receptor Mechanisms and Signaling
- Helicobacter pylori-related gastroenterology studies
- Nanocluster Synthesis and Applications
- Inhalation and Respiratory Drug Delivery
- Amyotrophic Lateral Sclerosis Research
- Calpain Protease Function and Regulation
- Oral microbiology and periodontitis research
The University of Melbourne
2014-2024
Mental Health Research Institute
2004-2013
Florey Institute of Neuroscience and Mental Health
2013
Biotechnology Institute
2008
Parks Victoria
2008
Lerøy (Norway)
2007
Stavros Niarchos Foundation
2007
Ambedkar University Delhi
2006
Johns Hopkins University
1999-2000
Johns Hopkins Medicine
1999-2000
In studies of Alzheimer's disease pathogenesis there is an increasing focus on mechanisms intracellular amyloid-β (Aβ) generation and toxicity. Here we investigated the inhibitory potential 42 amino acid Aβ peptide (Aβ 1-42 ) activity electron transport chain enzyme complexes in human mitochondria. We found that synthetic specifically inhibited terminal complex cytochrome c oxidase (COX) a dose-dependent manner was dependent presence Cu 2+ specific “aging” solution. Maximal COX inhibition...
Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles and amyloid plaques, which are abnormal protein deposits. The major constituent plaques neurotoxic beta-amyloid peptide (Abeta); genetics familial AD support a direct role for this in AD. Abeta neurotoxicity linked to hydrogen peroxide formation. coordinates redox active transition metals, copper iron, catalytically generate reactive oxygen species. chemical mechanism underlying process not well defined....
Alzheimer's disease is an age-related neurodegenerative disorder with its toxicity linked to the generation of amyloid-β peptide (Aβ). Within Aβ sequence, there a systemic repeat GxxxG motif, which theoretical studies have suggested may be involved in both aggregation and membrane perturbation, processes that been implicated toxicity. We synthesized modified peptides, substituting glycine for leucine residues within motif (GSL peptides). These GSL peptides undergo β-sheet fibril formation at...
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....
The Amyloid beta peptide (Abeta) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline associated with disease. Cu2+ ions can induce de novo aggregation Abeta into non-amyloidogenic aggregates and production a toxic species. mechanism by which mediates change from amyloid material toward induced poorly defined. Here we demonstrate that state Abeta1-42 at neutral pH governed Cu2+:peptide molar ratio. By probing content total aggregation, observed distinct...
Our previous studies showed that colistin-induced neurotoxicity involves apoptosis and oxidative damage. The present study demonstrates a neuroprotective effect of rapamycin against in vitro vivo. In mouse model, colistin treatment (18 mg/kg/d; 14 days) produced marked neuronal mitochondria damage the cerebral cortex increased activation caspase-9 -3. Rapamycin cotreatment (2.5 mg/kg/d) effectively reduced this neurotoxic effect. an neuroblastoma-2a (N2a) cell culture pretreatment (500 nM)...
Amyloid beta (Aβ) peptide is the major constituent of extracellular amyloid plaques deposited in brains Alzheimer's disease patients and central to pathogenic pathway causing this disease. The identity neurotoxic Aβ species remains elusive. We previously reported that toxicity correlates strongly with its neuronal cell binding leading us hypothesize death caused by a specific oligomeric species. To identify associated death, we treated mouse cortical cultures synthetic Aβ40 Aβ42 peptides...
The toxicity of the amyloid-β peptide (Aβ) is thought to be responsible for neurodegeneration associated with Alzheimer disease. Generation hydrogen peroxide has been implicated as a key step in toxic pathway. Aβ coordinates redox active metal ion Cu2+ catalytically generate H2O2. Structural studies on interaction Cu have suggested that coordination sphere about resembles site superoxide dismutase 1. To investigate potential role such structures Aβ, two novel Aβ40 peptides, Aβ40(HisτMe) and...
The amyloid beta peptide (Abeta) is toxic to neuronal cells, and it probable that this toxicity responsible for the progressive cognitive decline associated with Alzheimer's disease. However, nature of Abeta species its precise mechanism action remain be determined. It has been reported methionine residue at position 35 a pivotal role play in Abeta. We examined effect mutating valine Abeta42 (AbetaM35V). neurotoxic activity AbetaM35V on primary mouse cortical cells was enhanced, diminished...
Abstract Alzheimer's disease is characterised by the accumulation of amyloid‐β peptide, which cleaved from copper‐binding precursor protein. Recent in vivo and vitro studies have illustrated importance copper neuropathogenesis suggested a role for protein homeostasis. Amyloid‐β member multigene family, including amyloid precursor‐like proteins‐1 ‐2. The domain similar among family members, suggesting an overall conservation its function or activity. Here, we demonstrate that double knockout...
BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents first step in production β (Aβ) peptides. Previous reports, by us and others, have indicated that levels activity are increased brain cortex patients with Alzheimer's disease (AD). The association between oxidative stress (OS) AD has prompted investigations support potentiation expression enzymatic OS. Here, we established conditions to analyse effects mild, non-lethal OS on primary...
Background: Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered polymyxin therapy remains a priority area in antimicrobial chemotherapy. present study investigates the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity. Methods: impact pretreatment on apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated...
Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and homeostasis. Disturbed homeostasis occurs patients with disease, an X-linked disorder characterized by mental retardation, neurodegeneration, connective tissue disorders, early childhood death. Mutations ATP7A result malfunction of copper-requiring enzymes, such as tyrosinase copper/zinc superoxide dismutase. The first step the two-step amidation reaction carried out peptidylglycine alpha-amidating monooxygenase (PAM)...
Substantial evidence suggests that soluble oligomers of Aβ are the neurotoxic form resulting in progression Alzheimer's disease (AD). Tyrosine-10 has been identified as a pivotal residue neurotoxicity and dityrosine cross-linked dimers have proposed physiologically relevant species linked to AD. We describe synthesis characterization dityrosine-linked demonstrate that, contrast other covalently dimers, discrete, stable, aggregates. Furthermore, display increased toxicity neuronal cell-line...
Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation proteolytic signaling networks critical for excitotoxicity, identity affected proteins and mechanisms which they induce cell remain unclear. To address this, we used quantitative N-terminomics to identify modified proteolysis neurons undergoing excitotoxic death. We found that most proteolytically processed are likely...