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Neurotrophins in Alzheimer's disease

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The Coulson laboratory is investigating how and why certain neurons die in neurodegenerative diseases including Alzheimer’s disease (AD) and motor neuron disease (MND).

Our work is focused  on the p75 neurotrophin receptor (p75NTR) and its role in neuronal loss, particularly the nerve cell degeneration that occurs in cholinergic neurons in the brain and spinal cord. Why cholinergic neurons of the basal forebrain die in Alzheimer’s disease, what contribution their loss makes to cognitive decline, whether manipulating neurotrophic signalling (NGF, BDNF, TrkA/B, p75) can protect or restore cognitive function, and what role the neurotrophins play in the normal function of these neurons are questions we are researching.

Cholinergic neurons in the basal forebrain are important for learning and memory, and post-mortem studies show that they can be selectively lost in AD. The current treatment for AD patients targets the function of these cholinergic neurons. However, significant loss of these neurons has already occurred in the majority of AD patients prior to treatment, and because these drugs are only efficacious while the neurons are alive, these treatments are of limited value to most patients. Better drugs are needed. Similarly, cholinergic neurons in the spinal cord selectively die in MND, causing loss of muscle tone and paralysis. No treatments are effective in treating the underlying cell loss in this debilitating condition.

Obstructive sleep apnoea (OSA) is a significant risk factor for the development of Alzheimer’s Disease. Using a novel mouse model of OSA, we have discovered that induced intermittent hypoxia during sleep causes cholinergic basal forebrain neurons to die, resulting in cognitive decline and increased amyloid beta accumulation, both hallmarks of AD. The lab is focused on the mechanism by which cBF neurons die in OSA, the specific consequences of the degeneration and ultimately aim to identify diagnostic elements for the treatment of AD.

The Coulson group has developed a candidate therapy (called c29) to try to stop the p75NTR death signalling pathway and promote cholinergic neuron survival. They have had success in a mouse model of MND, showing that a three-month c29 infusion could keep dying motor neurons alive for longer, and that treatment delayed disease onset. They further demonstrated that when mice were given the early-version drug, a cell survival signalling pathway was activated, and the cell death signalling pathway used by the p75 protein to kill dying motor neurons was blocked. In addition, collaborators from the University of Adelaide found that a by-product of p75 was found in high levels in people with MND, and could be measured in urine and blood. The c29 treated mice also showed less of this by-product, indicating that motor neuron degeneration was not being activated to the same extent.

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Group leader

Professor Elizabeth Coulson

Professor Elizabeth Coulson

Group Leader, Neurotrophins in Alzheimer’s disease

Group Leader in Dementia Research, Clem Jones Centre for Ageing Dementia Research & Professor

  +61 7 336 53034
  elizabeth.coulson@uq.edu.au
  UQ Researcher Profile

  • delineation of p75 death signalling pathways

  • generation of genetically modified mice with modified p75 neurotrophin receptor function

  • generation and characterisation of a novel OSA mouse model

  • demonstration of a link between intermittent hypoxia and cholinergic basal forebrain neuron degeneration

  • development of a candidate therapy (called c29) that prevents p75NTR death signalling pathway and promotes cholinergic neuron survival in animal models of neurodegeneration.

The laboratory has expertise in neurotrophins and their signalling pathways, cholinergic basal forebrain neuron anatomy, function and manipulation, and in neurodegenerative disease particularly Alzheimer’s and motor neuron disease.

Below list of selected publications by date:

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Our approach

We use a range of techniques in our research including molecular and cellular biology, animal models, histology, neuronal network tracing, mouse cognitive testing and small animal MRI. In addition, we have selected projects that involve human participants or the analysis of human cohort data.

Aims to achieve

Our aim is to understand the causes and consequences of cholinergic basal forebrain neuron degeneration, with a focus on the role of neurotrophins in health and disease, in particular relating to dementia, with the long term objective to identify therapeutic strategies and compounds that can prevent or slow degeneration and cognitive impairment in humans.

Research areas

  • Neurodegenerative disease
  • Nerve cell survival
  • P75NTR biology
  • Regulation of neurodegeneration
  • Sleep disruption and Alzheimer’s Disease

News

Our team

Group Leader

  • Professor Elizabeth Coulson

    Group Leader in Dementia Research, Clem Jones Centre for Ageing Dementia Research & Professor
    Queensland Brain Institute
    Interim Head of School
    School Biomedical Science

Research Members

  • Dr Alice Zhou

    PhD Student & Postdoctoral Research Fellow
    Queensland Brain Institute

Students