Crouch Laboratory: Neurodegenerative Disease

Research Overview

The research focus of the Crouch laboratory is neurodegenerative disease.  Neurodegenerative disease involves progressive loss of function of the neuronal cells needed for our ability to think, move, breathe and swallow, and the most common forms include Alzheimer's disease, Huntington's disease, Parkinson's disease, and motor neuron disease.  Because the likelihood of developing neurodegenerative disease increases with increasing age, an ageing global population and an increasing life expectancy means that the incidence of neurodegenerative disease is escalating at an unprecedented rate. An unfortunate commonality shared by all neurodegenerative diseases is that effective therapeutics do not exist.  The ultimate objective of the Crouch laboratory is to complete research that will expedite the development of effective therapeutics.  To achieve this we undertake research in two key research areas; the testing of potential new therapeutics and the examination of impaired energy metabolism in neuronal failure.

Key Research Areas

Testing of potential new therapeutics

Working in close collaboration with chemists and biotechnology companies provides the Crouch laboratory with a unique opportunity to conduct pre-clinical studies using compounds under development as potential therapeutics for neurodegenerative disease.  These studies are conducted using in vitro and in vivo models of neurodegenerative disease.  The aim of these studies is to generate information on the mechanism of action for these compounds and to identify compounds that have the best potential to proceed further towards clinical testing.

Impaired energy metabolism in neuronal failure

A major obstacle in the development of therapeutics to treat neurodegenerative disease is that the cellular causes of neuronal failure in these diseases are incompletely understood.  An important part of our research therefore focuses on trying to define the processes that lead to neuronal failure. Neurons are the most energy hungry cells in the human body and a relatively small impediment to their ability to generate energy can have large effect on neuronal activity.  By using a range of cell culture models the aim of our research in this area of work is to examine the effects of impaired energy metabolism on cellular functions relative to neuronal activity.

Objectives

  • To conduct pre-clinical testing of compounds to define their potential as therapeutics to treat neurodegenerative disease.
  • To define the cellular mechanism of action of these potential therapeutics.
  • To examine the contribution of impaired energy metabolism to cellular dysfunction using in vitro and in vivo models of neurodegenerative disease.

Major Achievements

  • Showing treatment with a bis(thiosemicarbazone) compound attenuates disease symptoms in a mouse model of Alzheimer's disease.
  • Showing inhibition of the mitochondrial enzyme cytochrome c oxidase can be induced by exposure to a dimeric form of the Alzheimer's disease amyloid-beta peptide.
  • Showing the potential Alzheimer's disease therapeutic PBT2 acts as an ionophore to activate neuroprotective cell signaling events.

Techniques

  • Animal models of neurodegenerative disease
  • Cognitive and locomotor testing of animals
  • Cell culture
  • Western blot
  • Immunocytochemistry
  • Enzyme activity assays
  • Cell energy metabolism

Collaborators

National

  • Dr  Anthony White, Department of Pathology, University of Melbourne
  • Assoc.  Prof. Kevin Barnham, Department of Pathology, University of Melbourne
  • Dr Paul  Donnelly, School of Chemistry, University of Melbourne
  • Assoc.  Prof. Robert Cherny, Prana Biotechnology
  • Prof.  Ashley Bush, Mental Health Research Institute
  • Prof.  Colin Masters, Mental Health Research Institute
  • Assoc.  Prof. Anthony Hannan, Florey Neuroscience Institutes
  • Assoc.  Prof. Ian Trounce, Centre for Eye Research Australia

International

  • Prof. James Shen,  Academia Sinica, Taiwan

Funding

  • National Health and Medical  Research Council (2009-2013)
  • Bethlehem Griffiths Research  Foundation (2006, 2010-2011)
  • Brain Foundation (2011)
  • Motor Neuron Disease Research  Institute of Australia (2008, 2010-2011)
  • ANZ Charitable Trusts (Judith  Jane Mason & Harold Stannett Williams Memorial Foundation) (2011)
  • Melbourne Neuroscience  Institute (2011)
  • University of Melbourne (2007)
  • CASS Foundation (2009, 2010)

Research Publications

  • Crouch  PJ, Blake R, Duce JA, Ciccotosto GD, Li Q-X, Barnham KJ, Curtain CC, Cherny RA,  Cappai R, Dyrks T, Masters CL, Trounce IA. Copper-dependant inhibition of  human cytochrome c oxidase by a dimeric conformer of Aβ1-42. Journal of  Neuroscience 2005; 25: 672-679.
  • Crouch  PJ, Barnham KJ, Duce, JA, Blake RE, Masters CL, Trounce IA.   Copper-dependent inhibition of cytochrome c oxidase by Aβ1-42 requires reduced  methionine at residue 35 of the Aβ peptide. Journal of Neurochemistry 2006;  99: 226-236.
  • Crouch  PJ, Harding S-ME, White AR, Camakaris J, Bush AI, Masters CL.  Mechanisms  of Aβ mediated neurodegeneration in Alzheimer's disease. The International  Journal of Biochemistry and Cell Biology 2008;  40(2): 181-198.
  • Crouch  PJ, Hung LW, Adlard PA, Cortes M, Lal V, Filiz G, Perez KA, Nurjono M, Caragounis  A, Du T, Laughton K, Volitakis I, Bush AI, Li QX, Masters CL, Cappai R, Cherny,  RA, Donnelly PS, White AR, Branham KJ.  Increasing Cu bioavailability  inhibits Aβ oligomers and tau phosphorylation. Proceedings of the National  Academy of Sciences USA 2009;  106(2): 381-386.
  • Crouch  PJ, Tew DJ, Du T, Nguyen DN, Caragounis A, Filiz G, Blake RE, Trounce IA, Soon  CPW, Laughton K, Perez KA, Li QX, Cherny RA, Masters CL, Barnham KJ, White AR.   Restored degradation of the Alzheimer's amyloid-β peptide by targeting  amyloid formation. Journal of Neurochemistry 2009; 108: 1198-1207.
  • Adlard  PA, Bica L, White AR, Cappai R, Nurjuno M, Crouch PJ, Filiz G, Finkelstein DI,  Bush AI.   Metal ionophore treatment restores synaptic  plasticity in a mouse model of Alzheimer's disease. PLoS ONE 2011; 6(3): e17669.

Research Projects

Currently no project details available



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience, Molecular Mechanisms of Disease



Key Contact

For further information about this research, please contact Dr Peter Crouch

Department / Centre

Pathology