Quick Project Snapshot
Effect of Abeta on excitotoxic signalling pathways
The NMDA receptor (NMDAR) is a ligand-gated ion channel essential for normal synaptic function and is vital in learning and memory processes. However, when overstimulated, NMDARs are also responsible for a cascade of toxic events, termed “excitotoxicity”, which are triggered by the excessive entry of calcium into the cell through the receptor channel. Excitotoxicity is implicated in number of neurological disorders including Alzheimer’s disease (AD), in which the Abeta peptide, the major component of plaques in AD brain, has been proposed to enhance the activity of NMDARs. One consequence of excitotoxicity is the increased release of extracellular copper which may feedback on NMDARs to reduce calcium entry to the cell. Our laboratory works with novel compounds that modulate the copper status of cells, and which are neuroprotective in NMDAR excitotoxicity. These compounds appear to act primarily on downstream components in the calcium-signalling pathway rather than at the level of the NMDAR itself, such as the calpain and calcineurin system. This project will further probe the involvement of copper in calcium-mediated excitotoxicity, and determine how Abeta intersects with downstream components of this pathway. Skills learned will include cell culture techniques, western blotting and immunohistochemistry.
This laboratory has expertise in Medicinal Chemistry (in association with Prana Biotechnology) and in biomarker discovery. More recently, it has focussed on the pathways leading to Parkinson’s disease, especially around the oxidative modifications of tau.
The Australian Imaging, Biomarker and Lifestyle (AIBL) Study, the Dementia Collaborative Research Centres (DCRC) and the Cooperative Research Centre for Mental Health (CRCMH). AIBL, DCRC and the CRCMH are intimately involved in our research programs, relying on patient cohorts for biomarker and imaging discovery in both neurodegenerative and psychotic illness.
Translation of our research findings into clinical practice will become more important over the next five years, as we move from a series of failed or equivocal phase 3 drug trials sponsored by the pharmaceutical industry. There is now general agreement that these drug trials need to be based at the earliest possible stage of Alzheimer’s disease, hence our participation in the Dominantly Inherited Alzheimer Network (DIAN) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (the A4 study). These two pre-clinical trials are designed to administer drugs in the preclinical phases of both familial and sporadic Alzheimer’s disease.
All Projects by this LabEffect of Abeta on excitotoxic signalling pathwaysEffect of tau phosphorylation on exosome release in cell culture systemsThe influence of alpha-synuclein on olfactionThe role of peroxinitrite in depressionThe role of tau protein in olfactory processesAre exosomes driving Alzheimer’s disease pathogenesis?Discovering how toxic proteins traffic from cell to cell in Alzheimer’s disease.Uncovering the role of exosome derived lipids in Alzheimer’s disease.
Dr Lachlan Thompson
Prof David Finkelstein
Scientists in the Neurodegeneration division interrogate how neurones live, die and can be rescued to improve brain function in degenerative conditions such as Parkinson’s and Motor Neuron Diseases. There is no effective treatment for Motor Neurone Disease and the incidence of Parkinson’s Disease is rising alarmingly in our aging community. Gene abnormalities, energy deprivation, toxic rubbish accumulation and inflammation all contribute to a toxic environment for brain cells. Our teams study these events in animal models and cultured cells, with a view to translating knowledge into new therapies for human patients.