Quick Project Snapshot
Are exosomes driving Alzheimer’s disease pathogenesis?
Neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion disease have distinct clinical manifestations and molecular pathology; however they share common features such as aggregation of disease specific proteins. These include tau and β-amyloid (Aβ) in Alzheimer’s disease (AD), α-synuclein (α-syn) in Parkinson’s disease and the prion protein (PrP) in prion disease. Further commonalities exist, namely those observed at the anatomical level revealing spread of these proteins is in a non-random, topographically predictable manner in the brain. Cell-to-cell contact and passive spread were initially deemed responsible; however, more recently small extracellular vesicles, called exosomes, have been proposed to play a role.
Exosomes are released into the extracellular environment by most cell types and play an important role in inter-cellular communication. Once released from the donor cell, exosomes act as discrete vesicles travelling to distant and proximal recipient cells to alter cell function and phenotype. In the case of prion disease, we have shown that exosomes alter recipient cell function by transmitting infectious prions and initiating a cascade of events that further spreads and propagates the disease. The idea that exosomes may also be involved in the spreading of pathology from cell to cell in AD has recently gained considerable attention with tau and Aβ postulated to be trafficked via exosomes by many leaders in the AD field.
This project will take advantage of a new protocol we have developed to isolate and study exosomes in the human AD brain. Techniques employed will include exosome isolation from human and mouse tissue, western blotting, density gradients, dynamic light scattering and electron microscopy. The student will examine the content of brain derived exosomes in AD with the aim of determining the contribution of exosomes to the neurotoxicity and neuropathology that defines disease.
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.