Quick Project Snapshot
Discovering how toxic proteins traffic from cell to cell in Alzheimer’s disease.
Alzheimer’s disease (AD) is a progressive and unremitting neurodegenerative disorder characterized by impairments in cognition and memory. On a macroscopic level, widespread neuronal degeneration is interspersed with the presence of the key pathological hallmarks of AD: neurofibrillary tangles composed of hyperphosphorylated tau and amyloid plaques comprised of amyloid-β (Aβ).
Recent studies have strongly implicated cell-to-cell transmission of tau and Aβ in progression of AD, however the mechanism of transfer between cells is unclear.
Small extracellular vesicles, called exosomes, play an important role in cell to cell trafficking. Once released from the donor cell, exosomes act as discrete vesicles travelling to distant and proximal recipient cells to alter cell function and phenotype. The idea that exosomes may be involved in the spreading of pathology from cell to cell in AD has recently gained considerable attention with our recent findings suggesting tau and Aβ are associated with human brain derived exosomes.
This project aims to examine the effect of tau hyperphosphorylation and Aβ on the release of exosomes in cell culture systems, and to determine the potential impact of this mechanism in the propagation of pathology in Alzheimer’s disease. Techniques employed will include cell culture, the use of pharmacological tools to manipulate tau phosphorylation, western-blotting, and exosome isolation and characterisation using transmission electron microscopy and density gradients.
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.