The crucial role of the sleep-wake system in Alzheimer’s Disease pathophysiology

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This is one of two research projects exploring the sleep-wake cycle of patients with Alzheimer's disease. The University of Melbourne is the home institution for this project. To view the KU Leuven-based partner project, click here.

Alzheimer’s disease (AD) is the most common form of dementia. The amyloid hypothesis, that sees the accumulation and deposition of amyloid β (Aβ) peptide as the primary cause of Alzheimer's disease (AD), has been the predominant hypothesis in AD research for more than three decades with little success. Clinically, the focus in diagnosing and managing dementia has been on cognitive aspects of AD, although pre symptomatic symptoms (e.g. sleep wake dysregulation, hyperarousal and agitation) are clinically at least as relevant and manifest very early in disease.  The project will address these issues by using transgenic mice that model tauopathies (AD and FTD, frontotemporal dementia) which replicate early AD sleep dysregulation and agitation.  The project will also attempt to reduce hyperarousal and reset normal sleep wake balance by using clinically effective orexin receptor antagonists.

Project goals

To improve disease treatment, by normalizing the sleep-wake cycle of the patients: this would be of great benefit for the patients, but also their carers. In addition, if treatment were to start sufficiently early, before full-blown pathology and cognitive decline are established, it may even help to delay disease onset. It is suggested that by improving sleep at night, especially deep or SWS (slow wave sleep), brain clearance of toxic metabolites by the glymphatic system, e.g. phosphorylated amyloid and Tau, may delay disease onset by inhibiting the spread of toxic amyloid and Tau throughout the brain25:

Research questions:

  1. Whether acute orexin receptor blockade in established mouse tauopathy models with the clinical orexinergic hypnotic suvorexant is effective and whether or not it is orexin receptor subtype-dependent.
  2. Whether targeting specifically brain sleep wake centres using chemogenetics is sufficient to explain the effects of orexin receptor antagonists.
  3. Whether chronic dual or selective orexin receptor blockade during early stages of disease in rTg4510 mice have a disease modifying effect on sleep dysregulation and the development of Tau / AD pathology.

Supervision team

The University of Melbourne: Associate Professor Laura Jacobson

*Click on the researcher's name above to learn more about their publication and grant successes.

KU Leuven: Associate Professor Maarten Van Den Bossche

Who we are looking for

We are seeking a PhD candidate with the following skills:

  • Demonstrated experience in the field of neuroscience/psychological sciences.
  • Demonstrated experience with scientific computation.
  • Demonstrated ability to work independently and as part of a team.
  • Demonstrated time and project management skills.
  • Demonstrated ability to write research reports or other publications to a publishable standard (even if not published to date).
  • Excellent written and oral communication skills.
  • Demonstrated organisational skills, time management and ability to work to priorities.
  • Demonstrated problem-solving abilities.

Further details

The PhD candidate will benefit from the combined expertise of the project supervisors, and the embedding into two research environments.

Associate Professor Laura Jacobson shares an interest in the hypothesis that changes in the sleep-wake system have a fundamental role in the etiology, progression and symptomatology of neurodegenerative disorders.  For over 25 years there have been ongoing collaborations with the discoverer of orexin, Luis de Lecea and there are also extensive possibilities for collaborations with other Australian universities (like sleep researchers Professor Sharon Naismith and Professor Ron Grunstein at the University of Sydney).

Associate Professor Maarten Van Den Bossche will contribute his expertise in sleep and behavioural problems in dementia, which is fully intertwined with his clinical work on the clinical ward cog K for patients with dementia and severe neuropsychiatric symptoms and as the supervising psychiatrist at the Leuven University Centre for Sleep-Wake disorders at the University Hospital Leuven.

This PhD project will be based at the University of Melbourne with a minimum 12-month stay at KU Leuven.

The candidate will be enrolled in the PhD program at the Florey Department of Neuroscience and Mental Health at the University of Melbourne and in the PhD program at the Department of Neurosciences at KU Leuven.

To apply for this joint PhD opportunity, and to view the entry requirements, visit How to apply.

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