Understanding disease mechanisms

Dementia is a term that describes a clinical loss of cognitive function and can be caused by a number of different diseases. Each of these diseases is characterized by specific types of pathology in the brain. Understanding the basis of the development of pathology and cognitive decline is critical in determining targets for therapeutic intervention as well as clinical prognosis

Current projects

White matter and axon loss in Frontotemporal dementia (FTD), Motor Neuron Disease (MND) and other forms of dementia

Frontotemporal dementia (FTD) is an early onset dementia characterised by progressive deterioration of behaviour, personality and language with a relative sparing of memory. It is most common in people under the age of 65. FTD is caused by a number of different diseases and has genetic and pathological links to motor neurons disease (MND). A key characteristic of these diseases is the loss of nerve cell processes or axons and the protective coat that surrounds these, the myelin sheath. This project examines how the pathological proteins associated with these diseases, including TDP-43, tau and beta-amyloid, are linked to the degeneration of the axons. The role of the key myelinating cell of the central nervous system, the oligodendrocyte, is also under examination.

  • Objectives
  • Research Team: Associate Professor Anna King, Professor James Vickers, Dr Matthew Kirkcaldie, Dr Jackie Leung, Dr Nan Tian, Rachel Atkinson (student), Sam Dwyer (student), Hannah Dilger (student)
  • Collaborators: Associate Professor Julie Atkin, Professor Ian Blair, Associate Professor Nuri Gueven, Dr Jermeen Sreedharan, Professor Michael Coleman
  • Funding: Motor Neuron Disease Research Institute of Australia, Alzheimer's Australia Dementia Research Foundation, University of Tasmania

Excitability in AD

The incidence of AD increases with ageing the physiological changes that occur during ageing represent the background environment on which AD develops. In healthy ageing cognitive function and memory decline are associated with changes in the activity and morphology of nerve cells. This cognitive decline in healthy aging is variable from person to person at both the behavioural and cellular levels. To date we have only a fragmented picture of how the changes in neuronal connectivity, activity and morphology during aging relate to cognitive outcomes in healthy ageing. Further neuronal activity dysfunction is present in AD and likely underlies part of the progressive memory loss in AD. In particular, there is a subset of vulnerable pyramidal neurons that are more susceptible to AD pathology, degeneration and death in AD and the loss of these vulnerable neurons is strongly correlated with the severity of AD. Yet, so far no studies have investigated whether neuronal activity is differentially altered in this functionally important susceptible subpopulation of neurons. We are using behavioural cognitive testing, electrophysiology and detailed morphological analysis of the vulnerable pyramidal neurons in a mouse model of AD to address this gap in our knowledge.

  • Objectives: To determine whether neurons vulnerable in AD exhibit a distinct signature of functional and morphological changes in healthy ageing and early AD.
  • Research Team: Dr Adele Woodhouse, Prof James Vickers, Kimberley Stuart (student)
  • Collaborators
  • Funding: Yulgilbar Foundation, Alzheimer's Australia Dementia Research Foundation, Wicking Dementia Centre, University of Tasmania.

Microglia in dementia

Microglia are the resident immune cells in the brain. They are highly dynamic cells which in the healthy brain constantly sample the microenvironment. In their immune function they are scavengers of debris, and recent research suggests that they may also play a role in maintaining the connections between nerve cells, the synapses. During inflammation, microglia become active and change their state. Just as the peripheral immune system is primed by exposure to pathogens, microglia of the CNS can be primed by life events. Chronic inflammation has been linked to the development of AD and other neurodegenerativie disease. In AD, microglia may become dystrophic which reduces their ability to regulate the microenvironment. This may result in the development of pathological changes in AD such as the build-up of amyloid plaques or alterations to synapses. Using rodent models, we are investigating how microglia age in health and disease, the effect of microglial priming on ageing and AD pathogenesis, and whether modulation of microglia reduces AD burden.

  • Objectives: To determine what comes first: The abnormal accumulation of proteins which stimulate microglia or do microglia go ‘offline' due to ageing and other priming events leading to altered phagocytic capacity and the accumulation of protein.
  • Research Team: Dr Jenna Ziebell, A/Prof Alison Canty, A/Prof Anna King, Prof James Vickers
  • Collaborators
  • Funding: Alzheimer's Australia Dementia Research Foundation, Wicking Dementia Centre, University of Tasmania.

Analysis tools for amyloid pathology

Much of the basic research into Alzheimer's and other diseases of the brain, relies on measuring and counting pathology and proteins we image using microscopes. Many of these measurements are based on techniques which are quite variable and prone to error, undermining the quality of the research and reducing its translatability. We use machine learning techniques to get the best possible measurement of the pathology of animal models of Alzheimer's disease, and by providing these tools to the research community free of charge, hope to improve the quality and power of research into potential treatments for this devastating disease.

  • Objectives: To develop analysis tools that improve our quantitation of pathology
  • Research Team: Dr Matthew Kirkcaldie, Assoc Prof Anna King, Prof James Vickers, Aidan O'Mara (student)
  • Collaborators
  • Funding: Wicking Dementia Centre, University of Tasmania.